Substituted alkylamine derivatives and methods of use

ABSTRACT

Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/261,339, filed Jan. 12, 2001, and No. 60/323,764filed Sep. 19, 2001 which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of pharmaceutical agents andspecifically relates to compounds, compositions, uses and methods fortreating cancer and angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

[0003] Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes ab1, Atk, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak,KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK,Yes, and Zap70. Inhibition of such kinases has become an importanttherapeutic target.

[0004] Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularization, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

[0005] At the center of the network regulating the growth anddifferentiation of the vascular system and its components, both duringembryonic development and normal growth, and in a wide number ofpathological anomalies and diseases, lies the angiogenic factor known asVascular Endothelial Growth Factor” (VEGF; originally termed ‘VascularPermeability Factor”, VPF), along with its cellular receptors (see G.Breier et al., Trends in Cell Biology, 6, 454-6 (1996)).

[0006] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein relatedto “Platelet-Derived Growth Factor” (PDGF); it is produced by normalcell lines and tumor cell lines; is an endothelial cell-specificmitogen; shows angiogenic activity in in vivo test systems (e.g. rabbitcornea); is chemotactic for endothelial cells and monocytes; and inducesplasminogen activators in endothelial cells, which are involved in theproteolytic degradation of extracellular matrix during the formation ofcapillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta Growth Factor”(PlGF) and VEGF-C.

[0007] VEGF receptors (VEGFR) are transmembranous receptor tyrosinekinases. They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1 (also known asflt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

[0008] A large number of human tumors, especially gliomas andcarcinomas, express high levels of VEGF and its receptors. This has ledto the hypothesis that the VEGF released by tumor cells stimulates thegrowth of blood capillaries and the proliferation of tumor endotheliumin a paracrine manner and through the improved blood supply, acceleratetumor growth. Increased VEGF expression could explain the occurrence ofcerebral edema in patients with glioma. Direct evidence of the role ofVEGF as a tumor angiogenesis factor in vivo is shown in studies in whichVEGF expression or VEGF activity was inhibited. This was achieved withanti-VEGF antibodies, with dominant-negative VEGFR-2 mutants whichinhibited signal transduction, and with antisense-VEGF RNA techniques.All approaches led to a reduction in the growth of glioma cell lines orother tumor cell lines in vivo as a result of inhibited tumorangiogenesis.

[0009] Angiogenesis is regarded as an absolute prerequisite for tumorswhich grow beyond a diameter of about 1-2 mm; up to this limit, oxygenand nutrients may be supplied to the tumor cells by diffusion. Everytumor, regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

[0010] Three principal mechanisms play an important part in the activityof angiogenesis inhibitors against tumors: 1) Inhibition of the growthof vessels, especially capillaries, into avascular resting tumors, withthe result that there is no net tumor growth owing to the balance thatis achieved between cell death and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11,77-114 (2001).

[0011] VEGF's are unique in that they are the only angiogenic growthfactors known to contribute to vascular hyperpermeability and theformation of edema. Indeed, vascular hyperpermeability and edema that isassociated with the expression or administration of many other growthfactors appears to be mediated via VEGF production.

[0012] Inflammatory cytokines stimulate VEGF production. Hypoxia resultsin a marked upregulation of VEGF in numerous tissues, hence situationsinvolving infarct, occlusion, ischemia, anemia, or circulatoryimpairment typically invoke VEGF/VPF-mediated responses. Vascularhyperpermeability, associated edema, altered transendothelial exchangeand macromolecular extravasation, which is often accompanied bydiapedesis, can result in excessive matrix deposition, aberrant stromalproliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability cansignificantly contribute to disorders with these etiologic features. Assuch, regulators of angiogenesis have become an important therapeutictarget.

[0013] Schipper U.S. Pat. No. 3,226,394, issued Dec. 28, 1965, describesanthranilamides as CNS depressants. Japanese patent JP2000256358describes pyrazole derivatives that block the calcium release-activatedcalcium channel. EP application 9475000, published Oct. 6, 1999,describes compounds as PGE₂ antagonists. PCT publication WO96/41795,published Dec. 27, 1996, describes benzamides as vasopressinantagonists. WO01/29009 describes aminopyridines as KDR inhibitors.WO01/30745 describes anthranilic acids as CGMP phosphodiesteraseinhibitors. WO00/02851, published Jan. 20, 2000 describesarylsulfonylamnoaryl amides as guanylate cyclase activators. WO98/45268describes nicotinamide derivatives as PDE4 inhibitors. WO98/24771describes benzamides as vasopressin antagonists.

[0014] U.S. Pat. No. 5,532,358, issued Jul. 2, 1996, describes thepreparation of2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamideas an intermediate for HIV inhibitors. Triazine-substituted amines aredescribed for their aggregating ability (J. Amer. Chem. Soc., 115,905-16 (1993). Substituted imidazolines were tested for theirantidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992).N-(4-Pyridyl)anthranilic amides were described in Chem Abstr. 97:109837(1981). PCT publication WO99/32477, published Jul. 1, 1999, describesanthranilamides as anti-coagulants. U.S. Pat. No. 6,140,351 describesanthranilamides as anti-coagulants. PCT publication WO099/62885,published Dec. 9, 1999, describes 1-(4-aminophenyl)pyrazoles asantiinflammatories. PCT publication WO00/39111, published Jul. 6, 2000,describes amides as factor Xa inhibitors. PCT publication WO00/39117,published Jul, 6, 2000, describes heteroaromatic amides as factor Xainhibitors. PCT publication WO00/27819, published May 18, 2000,describes anthranilic acid amides as VEGF inhibitors. PCT publicationWO00/27820 published May 18, 2000, describes N-aryl anthranilic acidamides as VEGF inhibitors. 7-Chloroquinolinylamines are described inFR2168227 as antiinflammatories. WO01/55114, published Aug. 2, 2001,describes nicotinamides for the treatment of cancer. WO01/55115,published Aug. 2, 2001, describes nicotinamides as inducers ofapoptosis. WO01/85715, published Nov. 15, 2001, describes substitutedpyridines and pyrimidines as anti-angiogenesis agents. PCT publicationWO01/85691 published Nov. 15, 2001, describes anthranilic amides as VEGFinhibitors. PCT publication WO01/85671 published Nov. 15, 2001,describes anthranyl amides as VEGF inhibitors. PCT publicationWO01/81311 published Nov. 1, 2001, describes anthranilic amides as VEGFinhibitors. However, compounds of the current invention have not beendescribed as inhibitors of angiogenesis such as for the treatment ofcancer.

DESCRIPTION OF THE INVENTION

[0015] A class of compounds useful in treating cancer and angiogenesisis defined by Formula I

[0016] wherein each of A¹ and A² is independently C, CH or N;

[0017] wherein ring A is selected from

[0018] a) 5- or 6-membered partially saturated heterocyclyl,

[0019] preferably dihydropyran, dihydrothienyl, dihydrofuryl,oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl,dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl,

[0020] b) 5- or 6-membered heteroaryl,

[0021] preferably

[0022] I) 5-membered heteroaryl selected from thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,triazolyl and isothiazolyl,

[0023] even more preferably 5-membered heteroaryl selected from

[0024] II) preferably 6-membered heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl,

[0025] even more preferably 6-membered heteroaryl selected from

[0026] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl

[0027] preferably tetrahydroquinolinyl,

[0028] d) 9- or 10-membered fused heteroaryl,

[0029] preferably

[0030] i) fused 9-membered fused heteroaryl selected from benzothienyl,benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl,indazolyl and isoindolyl, and

[0031] ii) fused 10-membered heteroaryl selected from quinolyl,isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl,

[0032] e) naphthyl, and

[0033] f) 4-, 5- or 6-membered cycloalkenyl,

[0034] preferably 5-membered cycloalkenyl,

[0035] more preferably cyclopentadienyl or cyclopentenyl;

[0036] wherein X is selected from

[0037] preferably X is selected from

[0038] more preferably X

[0039] wherein Z is oxygen or sulfur;

[0040] wherein Y is selected from

[0041] preferably Y is selected from

[0042] more preferably Y is selected from

[0043] even more preferably Y is —NH—CH₂—;

[0044] wherein R^(a) and R^(b) are independently selected from H, halo,cyano and C₁₋₄-alkyl substituted with R², or wherein R^(a) and R^(b)together form C₃-C₄ cycloalkyl,

[0045] preferably H, halo, cyano and C₁₋₂-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₄ cycloalkyl, more preferablyH, halo and C₁-C₂-alkyl, even more preferably H;

[0046] wherein R^(z) is selected from C₁-C₄ alkylenyl, where one of theCH₂ groups may be substituted with an oxygen atom or an —NH—,

[0047] preferably C₁-C₂ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH— more preferably C₁-C₂alkylenyl;

[0048] wherein R^(d) is cycloalkyl, preferably C₃-C₆ cycloalkyl;

[0049] wherein R is selected from

[0050] a) substituted or unsubstituted 5-6 membered heterocyclyl,

[0051] preferably substituted or unsubstituted 5-6 membered heteroarylcomprising one or more nitrogen atoms,

[0052] more preferably 4-pyrazolyl, triazolyl, 4-pyridyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl, or 6-pyridazinyl,

[0053] even more preferably 4-pyridyl, 4-pyrimidinyl and 4-pyridazinyl,

[0054] even more preferably 4-pyridyl, and

[0055] b) substituted or unsubstituted fused 9-, 10- or 11-memberedheterocyclyl,

[0056] preferably substituted or unsubstituted 9-10 membered fusedheteroaryl comprising one or more nitrogen atoms,

[0057] more preferably indazolyl, quinolinyl, isoquinolinyl, orquinazolinyl,

[0058] even more preferably indazolyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 4-isoquinolyl, 5-isoquinolyl, and 6-isoquinolyl,

[0059] wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —SO₂R³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, lower alkyl substituted with R², cyano, nitro, loweralkenyl and lower alkynyl;

[0060] preferably halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, —NR³C(O)NR³R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl;

[0061] wherein R¹ is selected from

[0062] a) substituted or unsubstituted 6-10 membered aryl,

[0063] preferably phenyl, naphthyl, indenyl, or tetrahydronaphthyl,

[0064] more preferably phenyl,

[0065] b) substituted or unsubstituted 5-6 membered heterocyclyl,

[0066] preferably 5-6 membered heteroaryl,

[0067] more preferably thienyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, orpyrrolyl,

[0068] c) substituted or unsubstituted 9-10 membered fused heterocyclyl,

[0069] preferably 9-10 membered fused heteroaryl,

[0070] more preferably indazolyl, indolyl, 2,1,3-benzothiadiazolyl,isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, orquinazolinyl,

[0071] d) cycloalkyl, and

[0072] e) cycloalkenyl

[0073] wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl,

[0074] preferably R¹ is unsubstituted or substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —SO₂R³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³), —(C₁-C₂alkylenyl) NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitroand C₁₋₂-haloalkyl,

[0075] more preferably R¹ is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, bromo, methoxy,phenyloxy, benzyl, methylthio, methyl, ethyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy,aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl,cyclohexyl, piperidinyl, morpholinyl, N-methylpiperazinyl,N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, methylaminothiocarbonyl,N-methylamino-methylenyl, optionally substituted phenyl,N,N-diethylamino, or N,N-dimethylamino;

[0076] wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl,

[0077] preferably R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl,C₂₋₃-alkynyl and C₁₋₂-haloalkyl;

[0078] wherein R³ is selected from H, lower alkyl, phenyl, 5-6 memberedheterocyclyl, C₃-C₆ cycloalkyl, and lower haloalkyl,

[0079] preferably H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl, andC₁₋₂-haloalkyl,

[0080] more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, andtrifluoromethyl;

[0081] wherein R⁴ is independently selected from C₂₋₄-alkylenyl,C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of the CH₂ groups maybe substituted with an oxygen atom or an —NH—,

[0082] preferably C₂₋₃-alkylenyl where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—,

[0083] more preferably C₂-C₃ alkylenyl;

[0084] wherein R⁵ is selected from H, lower alkyl, phenyl and loweraralkyl,

[0085] preferably H, methyl or ethyl;

[0086] wherein R⁶ is selected from H or C₁₋₆-alkyl,

[0087] preferably H or C₁₋₂ alkyl; and

[0088] wherein R^(c) is selected from H, methyl and optionallysubstituted phenyl;

[0089] wherein R¹⁴ is selected from H, phenyl, 5-6 membered heterocyclyland C₃-C₆ cycloalkyl;

[0090] wherein p is 0 to 2, preferably p is 2;

[0091] and pharmaceutically acceptable salts thereof;

[0092] provided A is not naphthyl when X is —C(O)NH— and when R¹ isphenyl when Y is —NHCH₂— and when R is 4-pyridyl; further provided A isnot pyridyl when X is —C(O)NH— and when R¹ is4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is —N(CH₃)—and when R is 4-methylpiperidinyl; further provided A is not pyridylwhen X is —C(O)NH— and when Y is —NHCH₂— and when R is4-pyridylpiperidin-4-yl, 1-tertbutylpiperidin-4-yl,1-isopropylpiperidin-4-yl or 1-cycloalkylpiperidin-4-yl; furtherprovided A is not pyridyl when X is —C(O)NH— and when R¹ is4-[3-(3-pyridyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is—NHCH₂— and when R is 4-pyridyl; and further provided R is notunsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl.

[0093] The invention also relates to compounds of Formula II

[0094] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0095] preferably H;

[0096] wherein n is 0-2;

[0097] preferably 1-2;

[0098] wherein R is selected from

[0099] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0100] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0101] preferably 4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0102] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0103] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0104] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0105] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0106] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0107] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0108] wherein R² is one or more substituents independently selectedfrom

[0109] H,

[0110] halo,

[0111] C₁₋₆-alkyl,

[0112] C₁₋₆-haloalkyl,

[0113] C₁₋₆-alkoxy,

[0114] C₁₋₆-haloalkoxy,

[0115] C₁₋₆-carboxyalkyl,

[0116] unsubstituted or substituted aryl and

[0117] unsubstituted or substituted 5-6 membered heteroaryl;

[0118] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0119] wherein R⁶ is H or C₁₋₂-alkyl;

[0120] and pharmaceutically acceptable isomers and salts thereof.

[0121] The invention also relates to compounds of Formula III

[0122] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0123] preferably H;

[0124] wherein n is 0-2;

[0125] preferably 1-2;

[0126] wherein R is selected from

[0127] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0128] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0129] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0130] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0131] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0132] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0133] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0134] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0135] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0136] wherein R² is one or more substituents independently selectedfrom

[0137] H,

[0138] halo,

[0139] C₁₋₆-alkyl,

[0140] C₁₋₆-haloalkyl,

[0141] C₁₋₆-alkoxy,

[0142] C₁₋₆-haloalkoxy,

[0143] C₁₋₆-carboxyalkyl,

[0144] unsubstituted or substituted aryl and

[0145] unsubstituted or substituted 5-6 membered heteroaryl;

[0146] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0147] wherein R⁶ is H or C₁₋₂-alkyl;

[0148] and pharmaceutically acceptable isomers and salts thereof.

[0149] The invention also relates to compounds of Formula IV

[0150] wherein A³ is selected from CR² and N;

[0151] wherein A⁴ is selected from CR² and N; provided one of A³ and A⁴is not CR²;

[0152] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0153] preferably H;

[0154] wherein n is 0-2;

[0155] preferably 1-2;

[0156] wherein R is selected from

[0157] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0158] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0159] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0160] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0161] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0162] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0163] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0164] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;

[0165] wherein R² is one or more substituents independently selectedfrom

[0166] H,

[0167] halo,

[0168] C₁₋₆-alkyl,

[0169] C₁₋₆-haloalkyl,

[0170] C₁₋₆-alkoxy,

[0171] C₁₋₆-haloalkoxy,

[0172] C₁₋₆-carboxyalkyl,

[0173] unsubstituted or substituted aryl and

[0174] unsubstituted or substituted 5-6 membered heteroaryl;

[0175] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0176] wherein R⁶ is H or C₁₋₂-alkyl;

[0177] and pharmaceutically acceptable isomers and salts thereof.

[0178] The invention also relates to compounds of Formula V

[0179] wherein A⁵ is selected from S, O and NR⁶;

[0180] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0181] preferably H;

[0182] wherein n is 0-2;

[0183] preferably 1-2;

[0184] wherein R is selected from

[0185] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0186] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0187] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0188] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0189] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0190] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0191] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0192] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0193] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0194] wherein R² is one or more substituents independently selectedfrom

[0195] H,

[0196] halo,

[0197] C₁₋₆-alkyl,

[0198] C₁₋₆-haloalkyl,

[0199] C₁₋₆-alkoxy,

[0200] C₁₋₆-haloalkoxy,

[0201] C₁₋₆-carboxyalkyl,

[0202] unsubstituted or substituted aryl and

[0203] unsubstituted or substituted 5-6 membered heteroaryl;

[0204] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0205] wherein R⁶ is H or C₁₋₂-alkyl;

[0206] and pharmaceutically acceptable isomers and salts thereof.

[0207] The invention also relates to compounds of Formula VI

[0208] wherein A⁵ is selected from S, O and NR⁶;

[0209] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0210] preferably H;

[0211] wherein n is 0-2;

[0212] preferably 1-2;

[0213] wherein R is selected from

[0214] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0215] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0216] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0217] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0218] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0219] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0220] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0221] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0222] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0223] wherein R² is one or more substituents independently selectedfrom

[0224] H,

[0225] halo,

[0226] C₁₋₆-alkyl,

[0227] C₁₋₆-haloalkyl,

[0228] C₁₋₆-alkoxy,

[0229] C₁₋₆-haloalkoxy,

[0230] C₁₋₆-carboxyalkyl,

[0231] unsubstituted or substituted aryl and

[0232] unsubstituted or substituted 5-6 membered heteroaryl;

[0233] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0234] wherein R⁶ is H or C₁₋₂-alkyl;

[0235] and pharmaceutically acceptable isomers and salts thereof.

[0236] The invention also relates to compounds of Formula VII

[0237] wherein A⁵ is selected from S, O and NR⁶;

[0238] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N (R⁶)₂,

[0239] preferably H;

[0240] wherein n is 0-2;

[0241] preferably 1-2;

[0242] wherein R is selected from

[0243] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0244] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0245] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0246] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0247] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0248] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0249] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0250] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;

[0251] wherein R² is one or more substituents independently selectedfrom

[0252] H,

[0253] halo,

[0254] C₁₋₆-alkyl,

[0255] C₁₋₆-haloalkyl,

[0256] C₁₋₆-alkoxy,

[0257] C₁₋₆-haloalkoxy,

[0258] C₁₋₆-carboxyalkyl,

[0259] unsubstituted or substituted aryl and

[0260] unsubstituted or substituted 5-6 membered heteroaryl;

[0261] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0262] wherein R⁶ is H or C₁₋₂-alkyl;

[0263] and pharmaceutically acceptable isomers and salts thereof.

[0264] The invention also relates to compounds of Formula VIII

[0265] wherein A⁵ is selected from S, O and NR⁶;

[0266] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0267] preferably H;

[0268] wherein n is 0-2;

[0269] preferably 1-2;

[0270] wherein R is selected from

[0271] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0272] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0273] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0274] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0275] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0276] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0277] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0278] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0279] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0280] wherein R² is one or more substituents independently selectedfrom

[0281] H,

[0282] halo,

[0283] C₁₋₆-alkyl,

[0284] C₁₋₆-haloalkyl,

[0285] C₁₋₆-alkoxy,

[0286] C₁₋₆-haloalkoxy,

[0287] C₁₋₆-carboxyalkyl,

[0288] unsubstituted or substituted aryl and

[0289] unsubstituted or substituted 5-6 membered heteroaryl;

[0290] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0291] wherein R⁶ is H or C₁₋₂-alkyl;

[0292] and pharmaceutically acceptable isomers and salts thereof.

[0293] The invention also relates to compounds of Formula IX

[0294] wherein A⁵ is selected from S, O and NR⁶;

[0295] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0296] preferably H;

[0297] wherein n is 0-2;

[0298] preferably 1-2;

[0299] wherein R is selected from

[0300] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0301] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0302] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0303] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0304] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0305] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0306] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0307] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0308] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0309] wherein R² is one or more substituents independently selectedfrom

[0310] H,

[0311] halo,

[0312] C₁₋₆-alkyl,

[0313] C₁₋₆-haloalkyl,

[0314] C₁₋₆-alkoxy,

[0315] C₁₋₆-haloalkoxy,

[0316] C₁₋₆-carboxyalkyl,

[0317] unsubstituted or substituted aryl and

[0318] unsubstituted or substituted 5-6 membered heteroaryl;

[0319] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and

[0320] wherein R⁶ is H or C₁₋₂-alkyl;

[0321] and pharmaceutically acceptable isomers and salts thereof.

[0322] The invention also relates to compounds of Formula X

[0323] wherein A⁵ is selected from S, O and NR⁶;

[0324] wherein A⁶ is selected from N and CR²;

[0325] wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂,

[0326] preferably H;

[0327] wherein n is 0-2;

[0328] preferably 1-2;

[0329] wherein R is selected from

[0330] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl, and

[0331] b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl,

[0332] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl orquinozalinyl,

[0333] where R is substituted with one or more substituents selectedfrom halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy,

[0334] preferably substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy;

[0335] wherein R¹ is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl,

[0336] preferably unsubstituted or substituted phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl,

[0337] wherein R¹ is substituted with one or more substituents selectedfrom halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,

[0338] preferably chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy;

[0339] wherein R² is one or more substituents independently selectedfrom

[0340] H,

[0341] halo,

[0342] C₁₋₆-alkyl,

[0343] C₁₋₆-haloalkyl,

[0344] C₁₋₆-alkoxy,

[0345] C₁₋₆-haloalkoxy,

[0346] C₁₋₆-carboxyalkyl,

[0347] unsubstituted or substituted aryl and

[0348] unsubstituted or substituted 5-6 membered heteroaryl;

[0349] preferably one or more substituents independently selected fromH, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl;

[0350] wherein

[0351] wherein R⁶ is H or C₁₋₂-alkyl;

[0352] and pharmaceutically acceptable isomers and salts thereof.

[0353] The invention also relates to compounds of Formula II′

[0354] wherein R is selected from

[0355] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl,

[0356] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl,triazolyl, and pyridazinyl,

[0357] more preferably 4-pyridyl, and

[0358] b) unsubstituted or substituted 9- or 10-membered fusedheterocyclyl

[0359] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,benzotriazolyl, 2,3-dihydrobenzofuryl, 2-oxo-1,2-dihydroquinol-7-yl,naphthyridinyl and quinozalinyl,

[0360] where substituted R is substituted with one or more substituentsselected from halo, amino, hydroxy, oxo, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, optionally substituted heterocyclyl-C₁₋₆-alkoxy, optionallysubstituted heterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆--alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl,

[0361] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy,dimethylaminoethoxyethoxy, methoxy and ethoxy;

[0362] wherein R¹ is selected from unsubstituted or substituted aryl,preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,cycloalkyl, preferably cyclohexyl,

[0363] 5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl,thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl,and

[0364] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl,naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl andbenzthiazolyl;

[0365] wherein substituted R¹ is substituted with one or moresubstituents selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkylenyl, optionally substituted 4-6membered heterocyclyl-C₂-C₄-alkenylenyl, optionally substituted 4-6membered heterocyclyl, optionally substituted phenyloxy, optionallysubstituted 4-6 membered heterocyclyloxy, optionally substituted 4-6membered heterocyclyl-C₁₋₄-alkyloxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, —NHC(O)NH₂, alkylcarbonylamino, hydroxy, oxo, cyano,aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,C₁₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

[0366]  and C₁₋₄-alkoxy,

[0367] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;

[0368] wherein R² is one or more substituents independently selectedfrom

[0369] H,

[0370] halo,

[0371] hydroxy,

[0372] amino,

[0373] C₁₋₆-alkyl,

[0374] C₁₋₆-haloalkyl,

[0375] C₁₋₆-alkoxy,

[0376] C₁₋₂-alkylamino,

[0377] aminosulfonyl,

[0378] C₃₋₆-cycloalkyl,

[0379] cyano,

[0380] C₁₋₂-hydroxyalkyl,

[0381] nitro,

[0382] C₂₋₃-alkenyl,

[0383] C₂₋₃-alkynyl,

[0384] C₁₋₆-haloalkoxy,

[0385] C₁₋₆-carboxyalkyl,

[0386] 5-6-membered heterocyclyl-C₁₋₆-alkylamino,

[0387] unsubstituted or substituted phenyl and

[0388] unsubstituted or substituted 5-6 membered heterocyclyl;

[0389] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl;

[0390] wherein R⁴ is selected from a direct bond, C₁₋₄-alkyl, and

[0391]  preferably a direct bond, ethyl, butyl, and

[0392] wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl,

[0393] preferably methylenyl, ethylenyl,

[0394]  and aminoethylenyl;

[0395] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl,

[0396] preferably trifluoromethyl; and

[0397] wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally substituted4-6 membered heterocyclyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl;

[0398] provided R² is not H, or provided R¹ is not heteroaryl or aryl orprovided R is substituted with optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, oroptionally substituted heterocyclyl-C₂₋₄-alkynyl, or R¹ is substitutedwith optionally substituted phenyloxy, optionally substituted 5-6membered heterocyclyloxy, optionally substituted 5-6 memberedheterocyclylsulfonyl, optionally substituted 5-6 memberedheterocyclylamino, optionally substituted 5-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy, orC₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₂-alkoxy; further provided R is not3-pyridyl when R^(z) is CH₂;

[0399] and pharmaceutically acceptable isomers and derivatives thereof.

[0400] The invention also relates to compounds of Formula XI

[0401] wherein R is selected from

[0402] a) unsubstituted or substituted 5- or 6-memberednitrogen-containing heteroaryl,

[0403] preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl,triazolyl, and pyridazinyl, more preferably 4-pyridyl, and

[0404] b) unsubstituted or substituted 9- or 10-membered fusedheteroaryl

[0405] preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,benzotriazolyl, naphthyridinyl and quinozalinyl,

[0406] where substituted R is substituted with one or more substituentsselected from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, optionally substituted heterocyclyl-C₁₋₆-alkoxy, optionallysubstituted heterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl,

[0407] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxydimethylaminoethoxyethoxy, methoxy and ethoxy;

[0408] wherein R¹ is selected from unsubstituted or substituted aryl,cycloalkyl,

[0409] 5-6 membered heteroaryl and

[0410] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,

[0411] preferably phenyl, tetrahydronaphthyl, indanyl, indenyl,naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl,thienyl, pyridyl, pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl,isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl,benzo[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl andbenzthiazolyl,

[0412] specifically 4-6 membered saturated or partially un-saturatedmonocyclic heterocyclyl,

[0413] 9-10 membered saturated or partially un-saturated bicyclicheterocyclyl, and

[0414] 13-14 membered saturated or partially un-saturated tricyclicheterocyclyl,

[0415] more specifically 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1H-indolyl,benzo[d]isothiazolyl, dihydro-benzimidazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, andtetrahydroquinolinyl,

[0416] wherein substituted R¹ is substituted with one or moresubstituents selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁₋₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

[0417]  and C₁₋₄-alkoxy,

[0418] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;

[0419] wherein R² is one or more substituents independently selectedfrom

[0420] H,

[0421] halo,

[0422] hydroxy,

[0423] amino,

[0424] C₁₋₆-alkyl,

[0425] C₁₋₆-haloalkyl,

[0426] C₁₋₆-alkoxy,

[0427] C₁₋₂-alkylamino,

[0428] aminosulfonyl,

[0429] C₃₋₆-cycloalkyl,

[0430] cyano,

[0431] C₁₋₂-hydroxyalkyl,

[0432] nitro,

[0433] C₂₋₃-alkenyl,

[0434] C₂₋₃-alkynyl,

[0435] C₁₋₆-haloalkoxy,

[0436] C₁₋₆-carboxyalkyl,

[0437] 5-6-membered heterocyclyl-C₁₋₆-alkylamino,

[0438] unsubstituted or substituted phenyl and

[0439] unsubstituted or substituted 5-6 membered heterocyclyl,

[0440] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl,

[0441] specifically chloro, fluoro, bromo, amino, hydroxy, methyl,ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl;

[0442] wherein R⁴ is selected from a direct bond, C₁₋₄-alkyl, and

[0443]  preferably a direct bond, ethyl, butyl, and

[0444] wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl,

[0445] preferably methylenyl, ethylenyl,

[0446]  and aminoethylenyl;

[0447] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl,

[0448] preferably trifluoromethyl; and

[0449] wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally substituted4-6 membered heterocyclyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkoxy-C₁₋₂-alkyl andC₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl;

[0450] provided R¹ is substituted with optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁₋₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy, orC₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy; further provided R is not3-pyridyl when R⁵ is CH₂;

[0451] and pharmaceutically acceptable isomers and derivatives thereof.

[0452] The invention also relates to compounds of Formula XII

[0453] wherein R¹ is selected from unsubstituted or substituted aryl,preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl,cycloalkyl, preferably cyclohexyl,

[0454] 5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl,thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl,and

[0455] 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl,naphthyridinyl, quinozalinyl, benzo [d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo [3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl;

[0456] wherein substituted R¹ is substituted with one or moresubstituents selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

[0457]  and C₁₋₄-alkoxy,

[0458] preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy;

[0459] wherein R² is one or more substituents independently selectedfrom

[0460] H,

[0461] halo,

[0462] hydroxy,

[0463] amino,

[0464] C₁₋₆-alkyl,

[0465] C₁₋₆-haloalkyl,

[0466] C₁₋₆-alkoxy,

[0467] C₁₋₂-alkylamino,

[0468] aminosulfonyl,

[0469] C₃₋₆-cycloalkyl,

[0470] cyano,

[0471] C₁₋₂-hydroxyalkyl,

[0472] nitro,

[0473] C₂₋₃-alkenyl,

[0474] C₂₋₃-alkynyl,

[0475] C₁₋₆-haloalkoxy,

[0476] C₁₋₆-carboxyalkyl,

[0477] 5-6-membered heterocyclyl-C₁₋₆-alkylamino,

[0478] unsubstituted or substituted phenyl and

[0479] unsubstituted or substituted 5-6 membered heterocyclyl,

[0480] preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, fury, pyridyl, imidazolyl, andpyrazolyl;

[0481] wherein R^(e) and R^(f) are independently selected from H andC₁₋₂-haloalkyl, preferably trifluoromethyl;

[0482] wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally substituted4-6 membered heterocyclyl, optionally substituted 4-6 memberedheterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkoxy-C₁₋₂-alkyl andC₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; and

[0483] wherein R²⁰ is one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl,

[0484] preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy,dimethylaminoethoxyethoxy, methoxy and ethoxy;

[0485] and pharmaceutically acceptable isomers and derivatives thereof.

[0486] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptablederivatives thereof as follows:

[0487] N-(4-Isopropylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0488]N-[3-(Isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0489]N-(3-Isoquinolyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0490]N-[4-Isopropylphenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0491]N-[4-(tert-Butyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0492]N-[4-(Methylpropyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0493]{2-[(2-(3-Pyridyl)ethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0494]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}carboxamide;

[0495]N-[5-(tert-Butyl)isoxazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0496]N-[5-(tert-Butyl)-1-methylpyrazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0497]N-[4-(tert-Butyl)(1,3-thiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0498]N-[5-(tert-Butyl)(1,3,4-thiadiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0499]N-[4-(4-Hydroxybutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0500]N-[2-(4-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0501]5-Bromo-N-[2-(4-chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0502]N-[2-(4-Phenoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0503]N-[2-(4-Methoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0504]N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0505]N-[2-(4-Hydroxy-3-ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0506]N-[2-(4-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0507]N-[2-(4-(tert-Butyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0508]N-[2-(3-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0509]N-[2-(3-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0510]N-[2-(3-(Trifluoromethyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0511]N-[2-(3-Ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0512]N-[2-(3,4-Dimethylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0513]N-[2-(1,3-Benzodioxol-5-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0514]N-[2-(4-Methylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0515]N-[2-(4-Hydroxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0516]N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0517]N-[2-(4-Bromophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0518]N-[2-(3,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0519]N-[2-(4-(Fluorosulfonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0520]N-[2-(3,5-(Dimethoxy)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0521]N-[2-(2,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0522]N-[2-(2-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0523]N-[2-(2-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0524]N-[2-(4-(Aminosulphonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0525]N-[2-(2-Thienyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0526]N-[2-(Pyridin-2-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)}carboxamide;

[0527]N-[2-(Pyridin-3-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0528]N-[2-(Pyridin-4-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0529]N-(4-Phenylbutyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0530]N-(2-Hydroxy-3-phenoxypropyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;

[0531]{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;

[0532]{5-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;

[0533]2-[(Pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamide;

[0534]N-(3,4-Dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0535]N-[4-(Morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0536]N-(4-{2-[(tert-Butoxy)carbonylamino]ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0537]N-[4-(2-Aminoethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0538]N-[4-(tert-Butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0539]N-[3-Amino-4-(tert-butyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0540]N-[4-(Isopropyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0541]N-(3-Aminosulfonyl-4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0542]N-{3-[(4-Methylpiperazinyl)sulfonyl]phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0543]N-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0544]N-[4-(1,1,2,2,3,3,4,4,4-Nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0545]N-[4-(Isopropyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamide;

[0546](2-{[2-(2-Pyridylamino)ethyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0547]{2-[(1-(2-Pyridyl)pyrrolidin-3-yl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0548]2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamide

[0549] {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(8-quinolyl)carboxamidehydrochloride;

[0550]N-[4-(4-Chlorophenoxy)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0551]{2-[(4-Pyridylmethyl)amino](3-pyridyl))-N-(2,3,4-trifluorophenyl)carboxamidehydrochloride;

[0552] N-(2-Naphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0553]N-(2-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0554]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(5,6,7,8-tetrahydronaphthyl)carboxamide hydrochloride;

[0555]N-(2H-Benzo[3,4-d]1,3-dioxolen-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0556] N-Naphthyl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0557]N-[3-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0558]N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0559]N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0560] N-Indan-2-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0561]N-[4-(tert-Butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0562]N-(4-sec-Butyl-phenyl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0563]N-(4-Methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0564]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-trifluoromethoxy)phenyl]carboxamide;

[0565]N-(4-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0566]N-(4-Butylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0567]N-(4-Iodophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0568]N-[3-(Hydroxyethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0569]N-(3-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0570] Ethyl2-methyl-5-[3-({2-[(4-pyridylmethyl)amino](3-pyridyl)}carbonylamino)phenyl]furan-3-carboxylate;

[0571]N-(3-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0572]N-[4-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0573]N-(6-Ethyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0574]N-(6-Propyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0575]N-[4-(tert-Butyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0576]N-(3-Hydroxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0577]N-[4-(Methylethyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0578]N-[3,5-bis(Trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0579]N-[4-Chloro-3-(trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0580]N-(3-Chlorophenyl){2-[(2-(4-pyridyl)ethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0581]N-(4-Phenoxyphenyl){2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0582]2-[(Benzo[b]thiophen-3-ylmethyl)amino](3-pyridyl)}-N-(4-phenoxyphenyl)carboxamide;

[0583]N-(4-Phenoxyphenyl){2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0584]N-[4-(Methylsulfonyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0585]N-(1-Acetylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0586] N-Indolin-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0587] N-Indol-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0588] N-Indol-5-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0589] N-Indol-7-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0590]N-[3-(tert-Butyl)pyrazol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0591]N-(3-Phenylpyrazol-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0592]N-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0593]N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0594]N-[3-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0595]N-[4-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide;

[0596]N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0597]N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;

[0598]N-[1-(2-Piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0599]N-[1-(2-Piperidylacetyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0600]N-[3,3-Dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0601]N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0602]N-[3-(1-Methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0603]N-[4-(1,1-Dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0604]N-[4-(tert-Butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamide;

[0605]N-(4-Bromo-2-fluorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0606]N-[4-(tert-Butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide;

[0607]{2-[({2-[3-(Dimethylamino)prop-1-ynyl](4-pyridyl)}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide;

[0608](2-{[(2-Methoxy(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide;

[0609]N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0610]N-[4-(tert-Butyl)-3-(3-piperid-1-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0611]N-[4-(tert-Butyl)-3-(3-pyrrolidin-1-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0612]N-[3-((1E)-4-Pyrrolidin-1-ylbut-1-enyl)-4-(tert-butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0613]N-[4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0614]N-[1-(2-Morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0615]N-[4-(tert-Butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;

[0616]N-(4-Chlorophenyl){2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;

[0617]{2-[(Pyrimidin-4-ylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0618]N-[4-(Isopropyl)phenyl]{4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide;

[0619](2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(tert-butyl)phenyl]carboxamide;

[0620]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide;

[0621](2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0622]N-[4-(tert-Butyl)phenyl]{6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0623]{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;

[0624]{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0625]N-(1-Bromo(3-isoquinolyl)){6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;

[0626]N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0627]N-(4-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0628]N-(3-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0629]N-(4-Cyclohexylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0630]N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0631]N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0632]N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0633]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamidehydrochloride;

[0634]Methyl-4-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoatehydrochloride;

[0635]N-[4-(Isopropyl)phenyl]{2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;

[0636]N-[4-(tert-Butyl)phenyl]{2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide;

[0637]{2-[(6-Quinolylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;

[0638]N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;

[0639] N-phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;

[0640]N-(4-chlorophenyl)-3-[(4-pyridinylmethylene)amino]-4-pyridinecarboxamide;

[0641]N-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0642]N-(3,4-dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;

[0643]N-(3-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0644]N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide;

[0645]N-(4-chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide;

[0646]N-(3,4-dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide;

[0647]N-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0648]N-(3,4-dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0649]N-(3-fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0650]N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0651]N-(4-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0652]{6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide;

[0653]N-(3-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0654]N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide;

[0655]N-(3-fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;

[0656]N-(4-chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;

[0657]N-(4-chlorophenyl){2-[(5-quinolylmethyl)amino](3-pyridyl)}carboxamide;

[0658]N-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide;

[0659]N-(4-chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide;and

[0660]N-(4-chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide.

[0661] A family of specific compounds of particular interest withinFormula II′ consists of compounds and pharmaceutically-acceptablederivatives thereof as follows:

[0662]2-{[2-(1-Isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;

[0663]N-(4-tert-Butyl-phenyl)-2-{[2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0664]2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;

[0665]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-nicotinamide;

[0666]2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;

[0667]2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-methylpiperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;

[0668]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0669]2-({2-[2-(1-Methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;

[0670]N-(4-tert-Butyl-phenyl)-2-{[2-ethylpyridin-4-ylmethyl]-amino}-nicotinamide;

[0671]N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0672]2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0673]N-(4-Pentafluoroethyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0674]N-(4-tert-Butyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0675]N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0676]N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0677]N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl-ethylamino)-nicotinamide;

[0678]N-[3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0679]N-[3-(4-Boc-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0680]2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;

[0681]N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0682]2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0683]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0684]N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0685]N-(1-Boc-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0686]N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0687]N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0688]N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0689]N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0690]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;

[0691]N-[3,3-Dimethyl-1-(1-Boc-pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0692] N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0693]N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0694]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;

[0695]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;

[0696]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;

[0697]2-{[2-(3-Morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0698] (S)2-{[2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0699]N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0700]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0701]N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino)-nicotinamide;

[0702]N-(4-tert-Butyl-phenyl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0703]2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;

[0704]2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;

[0705]2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0706]N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0707]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0708]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0709]2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;

[0710]2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0711]2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide;

[0712] (R)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0713] (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0714] (R)N-[3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0715]N-[3-(1-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0716]N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0717]N-[3-tert-Butyl-4-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0718]N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0719]2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-trifluoromethyl-phenyl)-nicotinamide;

[0720]2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;

[0721]2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-tert-butyl-phenyl)-nicotinamide;

[0722]2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-tert-butyl-isoxazol-5-yl)-nicotinamide;

[0723]N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0724]2-[(Pyridin-4-ylmethyl)-amino]-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide;

[0725]N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0726]N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0727]N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0728]2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0729]N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0730]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0731]N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide;

[0732]2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;

[0733]2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;

[0734]N-(4-tert-Butyl-phenyl)-2-((2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;

[0735]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;

[0736]N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0737]2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide;

[0738]N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0739]N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0740]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;

[0741]N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidephosphate salt;

[0742]N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0743]N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide,hydrochloride;

[0744]{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamidehydrochloride;

[0745]Methyl-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoate,hydrochloride;

[0746]2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide;

[0747]N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0748]N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0749]2-{[2-(1-Benzohydrol-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide;

[0750]N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0751]N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0752]N-(3-tert-Butyl-isoxazol-5-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0753]N-(3-trifluoromethylphenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0754]2-[(2,3-Dihydro-benzofuran-6-ylmethyl)-amino]-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide;

[0755]N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidehydrochloride;

[0756] (R)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0757] (S)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0758]N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0759]N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0760]N-[4-Pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0761]2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamidehydrochloride;

[0762]N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0763]N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidehydrochloride;

[0764]2-[(Pyridin-4-ylmethyl)-amino]-N-(4-tert-butyl-phenyl)-nicotinamidehydrochloride;

[0765]N-[4-Trifluoromethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0766] (S)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0767] (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0768] (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0769]N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0770]N-(3-Trifluoromethyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0771]N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0772]N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide

[0773]N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0774]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide;

[0775]N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideedisylate;

[0776]N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0777]N-[4-tert-Butyl-3-(1-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0778]N-(3,3-Dimethyl-1,1,-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0779]N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0780]N-{4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0781]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;

[0782]N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0783]N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;

[0784]2-[(Pyridin-4-ylmethyl)-amino]-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamidehydrochloride;

[0785]N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0786]N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0787]N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0788]N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;

[0789]N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

[0790]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{(2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;

[0791]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0792]N-[3,3-Dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0793]N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0794]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;

[0795]N-[3,3-Dimethyl-1-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;

[0796]2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;

[0797]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0798]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamidehydrochloride;

[0799]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{([2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0800]N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;

[0801]N-(4-Pentafluoroethyl-phenyl)-2-[(pyrimidin-4-ylmethyl)-amino]-nicotinamide;

[0802]2-{[2-(Azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)nicotinamide;

[0803]N-(2,3,3-Trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide;

[0804]N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidehydrochloride;

[0805]N-[3,3-Dimethyl-1,1-dioxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;and

[0806]N-[2-(2-Dimethylamino-ethyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[0807] Indications

[0808] Compounds of the present invention would be useful for, but notlimited to, the prevention or treatment of angiogenesis relateddiseases. The compounds of the invention have kinase inhibitoryactivity, such as VEGFR/KDR inhibitory activity. The compounds of theinvention are useful in therapy as antineoplasia agents or to minimizedeleterious effects of VEGF.

[0809] Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

[0810] Preferably, the compounds are useful for the treatment ofneoplasia selected from lung cancer, colon cancer and breast cancer.

[0811] The compounds also would be useful for treatment ofophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,retrolental fibroplasia and neovascular glaucoma; retinal ischemia;vitreous hemorrhage; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including infantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the female reproductivesystem such as endometriosis. The compounds are also useful for thetreatment of edema, and conditions of vascular hyperpermeability.

[0812] The compounds of the invention are useful in therapy ofproliferative diseases. These compounds can be used for the treatment ofan inflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

[0813] These compounds can be used as active agents against such diseasestates as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, wound healing, peptic ulcer Helicobacter related diseases,fractures, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy ormacular degeneration. In addition, some of these compounds can be usedas active agents against solid tumors, malignant ascites, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma, characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome)) since such diseases require a proliferationof blood vessel cells for growth and/or metastasis.

[0814] Further, some of these compounds can be used as active agentsagainst burns, chronic lung disease, stroke, polyps, anaphylaxis,chronic and allergic inflammation, ovarian hyperstimulation syndrome,brain tumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

[0815] The compounds of the present invention are also useful in thetreatment of ulcers including bacterial, fungal, Mooren ulcers andulcerative colitis.

[0816] The compounds of the present invention are also useful in thetreatment of conditions wherein undesired angiogenesis, edema, orstromal deposition occurs in viral infections such as Herpes simplex,Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections andtoxoplasmosis, following trauma, radiation, stroke, endometriosis,ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis,synovitis, Crohn's disease, sickle cell anaemia, Lyme disease,pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendudisease, chronic inflammation, chronic occlusive pulmonary disease,asthma, and inflammatory rheumatoid or rheumatic disease. The compoundsare also useful in the reduction of sub-cutaneous fat and for thetreatment of obesity.

[0817] The compounds of the present invention are also useful in thetreatment of ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, glaucoma, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration.

[0818] The compounds of the present invention are also useful in thetreatment of cardiovascular conditions such as atherosclerosis,restenosis, arteriosclerosis, vascular occlusion and carotid obstructivedisease.

[0819] The compounds of the present invention are also useful in thetreatment of cancer related indications such as solid tumors, sarcomas(especially Ewing's sarcoma and osteosarcoma), retinoblastoma,rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, includingleukemia and lymphoma, tumor-induced pleural or pericardial effusions,and malignant ascites.

[0820] The compounds of the present invention are also useful in thetreatment of diabetic conditions such as diabetic retinopathy andmicroangiopathy.

[0821] The compounds of this invention may also act as inhibitors ofother protein kinases, e.g. p38, EGFR, CDK-2, CDK-5, IKK, JNK3, and thusbe effective in the treatment of diseases associated with other proteinkinases.

[0822] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0823] As used herein, the compounds of the present invention includethe pharmaceutically acceptable derivatives thereof.

[0824] Definitions

[0825] The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a preclinically evident stage ofdisorders in individuals).

[0826] The term “prevention” includes either preventing the onset ofdisorders altogether or delaying the onset of a preclinically evidentstage of disorders in individuals. This includes prophylactic treatmentof those at risk of developing a disease, such as a cancer, for example.“Prophylaxis” is another term for prevention.

[0827] A “pharmaceutically-acceptable derivative ” denotes any salt,ester of a compound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to inhibit angiogenesis.

[0828] The phrase “therapeutically-effective” is intended to qualify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies. For example, effective neoplastictherapeutic agents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

[0829] The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

[0830] Where the term “alkyl” is used, either alone or within otherterms such as “haloalkyl” and “alkylamino”, it embraces linear orbranched radicals having one to about twelve carbon atoms. Morepreferred alkyl radicals are “lower alkyl” radicals having one to aboutsix carbon atoms. Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, hexyl and the like. Even more preferred are lower alkylradicals having one or two carbon atoms. The term “alkylenyl” embracesbridging divalent alkyl radicals such as methylenyl and ethylenyl. Theterm “lower alkyl substituted with R²” does not include an acetalmoiety.

[0831] The term “alkenyl” embraces linear or branched radicals having atleast one carbon-carbon double bond of two to about twelve carbon atoms.More preferred alkenyl radicals are “lower alkenyl” radicals having twoto about six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

[0832] The term “alkynyl” denotes linear or branched radicals having atleast one carbon-carbon triple bond and having two to about twelvecarbon atoms. More preferred alkynyl radicals are “lower alkynyl”radicals having two to about six carbon atoms. Most preferred are loweralkynyl radicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

[0833] The term “halo” means halogens such as fluorine, chlorine,bromine or iodine atoms.

[0834] The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have either an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

[0835] The term “hydroxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more hydroxyl radicals. More preferredhydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one tosix carbon atoms and one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl. Even more preferred are lowerhydroxyalkyl radicals having one to three carbon atoms.

[0836] The term “alkoxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

[0837] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one or two rings wherein such rings may beattached together in a fused manner. The term “aryl” embraces aromaticradicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, andindanyl. More preferred aryl is phenyl. Said “aryl” group may have 1 to3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy and lower alkylamino. Phenyl substituted with —O—CH₂—O—forms the aryl benzodioxolyl substituent.

[0838] The term “heterocyclyl” embraces saturated, partially saturatedand unsaturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—, —O—S—or —S—S— portions. Said“heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

[0839] Examples of saturated heterocyclic radicals include saturated 3to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

[0840] Examples of unsaturated heterocyclic radicals, also termed“heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

[0841] The term also embraces radicals where heterocyclic radicals arefused/condensed with aryl radicals: unsaturated condensed heterocyclicgroup containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]; and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms[e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl anddihydrobenzofuryl]. Preferred heterocyclic radicals include five to tenmembered fused or unfused radicals. More preferred examples ofheteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl,thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferredheteroaryl radicals are 5- or 6-membered heteroaryl, containing one ortwo heteroatoms selected from sulfur, nitrogen and oxygen, selected fromthienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyland pyrazinyl.

[0842] Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

[0843] Particular examples of partially saturated and saturatedheterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

[0844] The term “sulfonyl”, whether used alone or linked to other termssuch as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.

[0845] The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotesa sulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂) The term “alkylaminosulfonyl” includes“N-alkylaminosulfonyl” where sulfamyl radicals are independentlysubstituted with one or two alkyl radical(s). More preferredalkylaminosulfonyl radicals are “lower alkylaminosulfonyl” radicalshaving one to six carbon atoms. Even more preferred are loweralkylaminosulfonyl radicals having one to three carbon atoms. Examplesof such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl,and N-ethylaminosulfonyl.

[0846] The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H.

[0847] The term “carbonyl”, whether used alone or with other terms, suchas “aminocarbonyl”, denotes —(C═O)—.

[0848] The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

[0849] The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl”denote aminocarbonyl radicals independently substituted with one or twoalkyl radicals, respectively. More preferred are “loweralkylaminocarbonyl” having lower alkyl radicals as described aboveattached to an aminocarbonyl radical.

[0850] The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl”denote aminocarbonyl radicals substituted, respectively, with one arylradical, or one alkyl and one aryl radical.

[0851] The term “heterocyclylalkylenyl” embracesheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkylenyl radicals are “5- or 6-memberedheteroarylalkylenyl” radicals having alkyl portions of one to six carbonatoms and a 5- or 6-membered heteroaryl radical. Even more preferred arelower heteroarylalkylenyl radicals having alkyl portions of one to threecarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

[0852] The term “aralkyl” embraces aryl-substituted alkyl radicals.Preferable aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms. Evenmore preferred are “phenylalkylenyl” attached to alkyl portions havingone to three carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

[0853] The term “alkylthio” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent sulfur atom. Even more preferred are lower alkylthio radicalshaving one to three carbon atoms. An example of “alkylthio” ismethylthio, (CH₃S—).

[0854] The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

[0855] The term “alkylamino” embraces “N-alkylamino” and“N,N-dialkylamino” where amino groups are substituted with one alkylradical and with two independent alkyl radicals, respectively. Morepreferred alkylamino radicals are “lower alkylamino” radicals having oneor two alkyl radicals of one to six carbon atoms, attached to a nitrogenatom. Even more preferred are lower alkylamino radicals having one tothree carbon atoms. Suitable alkylamino radicals may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino and the like.

[0856] The term “arylamino” denotes amino groups which have beensubstituted with one or two aryl radicals, such as N-phenylamino. Thearylamino radicals may be further substituted on the aryl ring portionof the radical.

[0857] The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

[0858] The term “aralkylamino” denotes amino groups which have beensubstituted with one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

[0859] The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino”denote amino groups which have been substituted with one aralkyl and onealkyl radical, or one aryl and one alkyl radical, respectively, to anamino group.

[0860] The term “aminoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

[0861] The term “alkylaminoalkyl” embraces alkyl radicals substitutedwith alkylamino radicals. More preferred alkylaminoalkyl radicals are“lower alkylaminoalkyl” radicals having alkyl radicals of one to sixcarbon atoms. Even more preferred are lower alkylaminoalkyl radicalshaving alkyl radicals of one to three carbon atoms. Suitablealkylaminoalkyl radicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl andthe like.

[0862] The term “alkylaminoalkoxy” embraces alkoxy radicals substitutedwith alkylamino radicals. More preferred alkylaminoalkoxy radicals are“lower alkylaminoalkoxy” radicals having alkoxy radicals of one to sixcarbon atoms. Even more preferred are lower alkylaminoalkoxy radicalshaving alkyl radicals of one to three carbon atoms. Suitablealkylaminoalkoxy radicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy andthe like.

[0863] The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicalssubstituted with alkylaminoalkoxy radicals. More preferredalkylaminoalkoxyalkoxy radicals are “lower alkylaminoalkoxyalkoxy”radicals having alkoxy radicals of one to six carbon atoms. Even morepreferred are lower alkylaminoalkoxyalkoxy radicals having alkylradicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy,N,N-diethylaminomethoxymethoxy and the like.

[0864] The term “carboxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more carboxy radicals. More preferredcarboxyalkyl radicals are “lower carboxyalkyl” radicals having one tosix carbon atoms and one carboxy radical. Examples of such radicalsinclude carboxymethyl, carboxypropyl, and the like. Even more preferredare lower carboxyalkyl radicals having one to three CH₂ groups.

[0865] The term “halosulfonyl” embraces sulfonyl radicals substitutedwith a halogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

[0866] The term “arylthio” embraces aryl radicals of six to ten carbonatoms, attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

[0867] The term “aralkylthio” embraces aralkyl radicals as describedabove, attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

[0868] The term “aryloxy” embraces optionally substituted aryl radicals,as defined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

[0869] The term “aralkoxy” embraces oxy-containing aralkyl radicalsattached through an oxygen atom to other radicals. More preferredaralkoxy radicals are “lower aralkoxy” radicals having optionallysubstituted phenyl radicals attached to lower alkoxy radical asdescribed above.

[0870] The term “heteroaryloxy” embraces optionally substitutedheteroaryl radicals, as defined above, attached to an oxygen atom.

[0871] The term “heteroarylalkoxy” embraces oxy-containingheteroarylalkyl radicals attached through an oxygen atom to otherradicals. More preferred heteroarylalkoxy radicals are “lowerheteroarylalkoxy” radicals having optionally substituted heteroarylradicals attached to lower alkoxy radical as described above.

[0872] The term “cycloalkyl” includes saturated carbocyclic groups.Preferred cycloalkyl groups include C₃-C₆ rings. More preferredcompounds include, cyclopentyl, cyclopropyl, and cyclohexyl.

[0873] The term “cycloalkenyl” includes carbocyclic groups having one ormore carbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

[0874] The term “comprising” is meant to be open ended, including theindicated component but not excluding other elements.

[0875] The phrase “Formula I-XII” includes sub formulas such as II′.

[0876] The compounds of the invention are endowed with kinase inhibitoryactivity, such as KDR inhibitory activity.

[0877] The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of KDR.

[0878] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-XII in association with a least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0879] The present invention also comprises a method of treatingangiogenesis related disorders in a subject having or susceptible tosuch disorder, the method comprising treating the subject with atherapeutically-effective amount of a compound of Formula I

[0880] wherein each of A¹ and A² is independently C, CH or N;

[0881] wherein ring A is selected from

[0882] a) 5- or 6-membered partially saturated heterocyclyl,

[0883] b) 5- or 6-membered heteroaryl,

[0884] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl,

[0885] d) 9-, 10- or 11-membered fused heteroaryl;

[0886] e) naphthyl, and

[0887] f) 4-, 5- or 6-membered cycloalkenyl;

[0888] wherein X is

[0889] wherein Z is oxygen or sulfur;

[0890] wherein Y is selected from

[0891] wherein p is 0 to 2,

[0892] wherein R^(a) and R^(b) are independently selected from H, halo,cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², or wherein R^(a) andR^(b) together form C₃-C₆ cycloalkyl;

[0893] wherein R^(z) is selected from C₂-C₆-alkylenyl, where one of theCH₂ groups may be replaced with an oxygen atom or an —NH—; wherein oneof the CH₂ groups may be substituted with one or two radicals selectedfrom halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R²;

[0894] wherein R^(d) is cycloalkyl;

[0895] wherein R is selected from

[0896] a) substituted or unsubstituted 5-6 membered heterocyclyl, b)substituted aryl, and

[0897] c) substituted or unsubstituted fused 9-14-membered bicyclic ortricyclic heterocyclyl;

[0898]  wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —SO₂R³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, nitro, alkylaminoalkoxyalkoxy, cyano,alkylaminoalkoxy, lower alkyl substituted with R², lower alkenylsubstituted with R², and lower alkynyl substituted with R²;

[0899] wherein R¹ is selected from

[0900] a) substituted or unsubstituted 6-10 membered aryl,

[0901] b) substituted or unsubstituted 5-6 membered heterocyclyl,

[0902] c) substituted or unsubstituted 9-14 membered bicyclic ortricyclic heterocyclyl,

[0903] d) cycloalkyl, and

[0904] e) cycloalkenyl,

[0905]  wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³ R³, —NH(C₁-C₄ alkylenyl R¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,halosulfonyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro,lower alkyl substituted with R², lower alkenyl substituted with R², andlower alkynyl substituted with R²;

[0906] wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl;

[0907] wherein R³ is selected from H, lower alkyl, phenyl, heterocyclyl,C₃-C₆-cycloalkyl, phenylalkyl, heterocyclylalkyl, C₃-C₆ cycloalkylalkyl,and lower haloalkyl;

[0908] wherein R⁴ is selected from a direct bond, C₂₋₄-alkylenyl,C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of the CH₂ groups maybe substituted with an oxygen atom or an —NH—, wherein R⁴ is optionallysubstituted with hydroxy;

[0909] wherein R⁵ is selected from H, lower alkyl, phenyl and loweraralkyl;

[0910] wherein R^(5a) is selected from H, lower alkyl, phenyl and loweraralkyl;

[0911] wherein R⁶ is selected from H or C₁₋₆-alkyl; and

[0912] wherein R¹⁴ is selected from H, phenyl, 5-6 membered heterocyclyland C₃-C₆ cycloalkyl;

[0913] and pharmaceutically acceptable derivatives thereof;

[0914] provided A is not naphthyl when X is —C(O)NH— and when R¹ isphenyl when Y is —NCH₂— and when R is 4-pyridyl; and further provided Ris not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is—NHCH₂—.

[0915] Combinations

[0916] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

[0917] The phrase “co-therapy” (or “combination-therapy”), in defininguse of a compound of the present invention and another pharmaceuticalagent, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as well to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule having a fixed ratio of these activeagents or in multiple, separate capsules for each agent.

[0918] Specifically, the administration of compounds of the presentinvention may be in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of neoplasia, such aswith radiation therapy or with cytostatic or cytotoxic agents.

[0919] If formulated as a fixed dose, such combination products employthe compounds of this invention within the accepted dosage ranges.Compounds of Formula I may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with, or after administration of the knownanticancer or cytotoxic agent.

[0920] Currently, standard treatment of primary tumors consists ofsurgical excision followed by either radiation or IV administeredchemotherapy. The typical chemotherapy regime consists of either DNAalkylating agents, DNA intercalating agents, CDK inhibitors, ormicrotubule poisons. The chemotherapy doses used are just below themaximal tolerated dose and therefore dose limiting toxicities typicallyinclude, nausea, vomiting, diarrhea, hair loss, neutropenia and thelike.

[0921] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which would be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.

[0922] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

[0923] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unfilmed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

[0924] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone,Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II,Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A,bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067,Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-MyersBMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1,Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin,Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa HakkoDC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41,doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954,Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa HakkoKT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American CyanamidLL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone,SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon KayakuNKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

[0925] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unfilmed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

[0926] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferonalfacon-1, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinide, filgrastim SDO1 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucinyttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

[0927] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors includingcelecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's,SOD mimics or α_(v)β₃ inhibitors.

[0928] The present invention comprises processes for the preparation ofa compound of Formula I-XII.

[0929] Also included in the family of compounds of Formula I-XII are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-XII may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic,pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxyethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI-XII include metallic salts, such as salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc, or salts made fromorganic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine. All of these salts may be prepared byconventional means from the corresponding compound of the invention byreacting, for example, the appropriate acid or base with the compound ofFormula I-XII.

[0930] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0931] Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.Preferred salts include hydrochloride, phosphate and edisylate.

[0932] Additional examples of such salts can be found in Berge et al.,J. Pharm. Sci., 66, 1 (1977).

GENERAL SYNTHETIC PROCEDURES

[0933] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-48, wherein the substituents areas defined for Formulas I-XII, above, except where further noted.

[0934] Cyclic amides can be prepared according to the method set out inScheme 1. The amino group of compound 1 (where R^(o) is alkyl, aryl, andthe like) is protected, such as with Boc anhydride, followed bytreatment, to remove the ester, such as with base, forming the protectedamine/free acid 2. Alternatively, other amino protecting groups known inthe art can be used. Substituted amines are coupled with the free acid,such as with EDC, to form the protected amine/amide 3. The protectedamine moiety is deprotected, such as with acid, and reacted via one stepreductive alkylation with carbonyl-containing compounds (where R′ is H,halo, cyano, —NHR⁶ and C₁₋₄ alkyl) to form the 1-amido-2-substitutedamino-compounds 4. Preferably the amination is in an alcohol, such asMeOH, EtOH or propanol, and at a temperature between about 0-50° C.,such as RT. Aldehydes or ketones are preferred carbonyl-containingcompounds. Alternative carbonyl-containing compounds are, for example,bisulfite adducts or hemiacetals, acetals, hemiketals or ketals ofcompounds with alcohols, for example lower hydroxyalkyl compounds; orthioacetals or thioketals of compounds with mercaptans, for examplelower alkylthio compounds. The reductive alkylation is preferablycarried out with hydrogenation in the presence of a catalyst, such asplatinum or especially palladium, which is preferably bonded to acarrier material, such as carbon, or a heavy metal catalyst, such asRaney nickel, at normal pressure or at pressures of from 0.1 to 10MegaPascal (MPa), or with reduction by means of complex hydrides, suchas borohydrides, especially alkali metal cyanoborohydrides, for examplesodium cyanoborohydride, in the presence of a suitable acid, preferablyrelatively weak acids, such as lower alkylcarboxylic acids, especiallyacetic acid, or a sulfonic acid, such as p-toluenesulfonic acid; incustomary solvents, for example alcohols, such as MeOH or EtOH, orethers, for example cyclic ethers, such as THF, in the presence orabsence of water.

[0935] Alternatively, compounds 4 can be prepared from mixed acid/amines5 as shown in Scheme 2. Substituted amines are coupled with the mixedacid/amines 5 such as with a coupling reagent, for example EDC, to formthe mixed amine/amide 6. Substituted carbonyl compounds, such as acidhalides, anhydrides, carboxylic acids, esters, ketones, aldehydes andthe like, are added to the mixed amine/amide 6 followed with reductionto give the substituted amide/substituted amine compounds 4.

[0936] Imino compounds 7 can be formed from the mixed amine/amides 6,such as by reacting with a substituted carbonyl compound.

[0937] Substituted cyclic carboxamides can be prepared from thecorresponding imino analogs by the process outlined in Scheme 4.Treatment of the imino compound 7 with a reducing agent yields compound4. Reagents which can be used to add hydrogen to an imine double bondinclude borane in THF, LiAlH₄, NaBH₄, sodium in EtOH and hydrogen in thepresence of a catalyst, and others.

[0938] Substituted carboxamides 4 can be prepared from the correspondinghalo analogs 8 by the process outlined in Scheme 5. Substituted aminoacids 9 are prepared from the corresponding chloro compounds 8 such asby reacting with an amine at a suitable temperature, such as about 80°C. The acid 9 is coupled with an amine, preferably in the presence of acoupling agent such as EDC, to form the corresponding amide 4.

[0939] The amination process can be carried out as an Ullmann typereaction using a copper catalyst, such as copper[0] or a copper[I]compound such as copper[I]oxide, copper[I]bromide or copper[I]iodide inthe presence of a suitable base (such as a metal carbonate, for exampleK₂CO₃) to neutralize the acid generated in the reaction. This reactionis reviewed in Houben-Weyl “Methoden der Organischen Chemie”, Band 11/1,page 32-33, 1958, in Organic Reactions, 14, page 19-24, 1965 and by J.Lindley (1984) in Tetrahedron, 40, page 1433-1456. The amount ofcatalyst is typically in the range of 1 to 20 mole percent. The reactionis carried out in an inert, aprotic solvent such as an ether (forexample dimethoxyethane or dioxane) or an amide (for exampledimethylformamide or N-methylpyrrolidone), under an inert atmosphere inthe temperature range of 60-180° C.

[0940] An alternative amination process involves using a Group VIIIelement, where the metal core of the catalyst should be a zero-valenttransition metal, such as palladium or nickel, which has the ability toundergo oxidative addition to the aryl-halogen bond. The zero valentstate of the metal may be generated in situ from the M[II] state. Thecatalyst complexes may include chelating ligands, such as alkyl, aryl orheteroaryl derivatives of phosphines or biphosphines, imines or arsines.Preferred catalysts contain palladium or nickel. Examples of suchcatalysts include palladium[II]chloride, palladium[II]acetate,tetrakis(triphenyl-phosphine)palladium[0] and nickel[II]acetylacetonate.The metal catalyst is typically in the range of 0.1 to 10 mole percent.The chelating ligands may be either monodentate, as in the case forexample of trialkyphosphines, such as tributylphosphine,triarylphosphines, such as tri-(ortho-tolyl)phosphine, and triheteroarylphosphines, such as tri-2-furylphosphine; or they may be bidentate suchas in the case of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferroceneand 1-(N,N-dimethyl-amino)-1′-(dicyclohexylphosphino)biphenyl. Thesupporting ligand may be complexed to the metal center in the form of ametal complex prior to being added to the reaction mixture or may beadded to the reaction mixture as a separate compound. The supportingligand is typically present in the range 0.01 to 20 mole percent. It isoften necessary to add a suitable base to the reaction mixture, such asa trialkylamine (for example DIEA or1,5-diazabicyclo[5,4,O]undec-5-ene), a Group I alkali metal alkoxide(for example potassium tert-butoxide) or carbonate (for example cesiumcarbonate) or potassium phosphate. The reaction is typically carried outin an inert aprotic solvent such as an ether (for exampledimethoxyethane or dioxane) or an amide (for example, DMF orN-methylpyrrolidone), under an inert atmosphere in the temperature rangeof 60-180° C.

[0941] The amination is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example DMF or dimethylacetamide, a cyclicether, for example THF or dioxane, or a nitrile, for example CH₃CN, orin a mixture thereof, at an appropriate temperature, for example in atemperature range of from about 40° C. to about 180° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0942] Substituted carboxamides 4 can be prepared from the correspondinghalo analogs 8 by the process outlined in Scheme 6. The chloro acid 8 iscoupled with an amine, preferably in the presence of a coupling agentsuch as EDC, to form the corresponding chloro amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10such as by reacting with an amine at a suitable temperature, such asabout 80° C. The amination reaction can be run in the presence of anappropriate catalyst such as a palladium catalyst, in the presence of anaprotic base such as sodium t-butoxide or cesium carbonate, or a nickelcatalyst, or a copper catalyst.

[0943] Substituted carboxamides 4 can be prepared from the correspondingbromo/chloro analogs 11 by the process outlined in Scheme 7. Thebromo/chloro acid 11 is coupled with an amine, preferably in thepresence of a coupling agent such as EDC, to form the correspondingbromo substituted amide 12. Suzuki coupling with the bromo amide 12 andsuitable boronic acids provides the substituted amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10as described in Scheme 6.

[0944] Substituted thiophenes 16 can be prepared by the method of Scheme8. The free amino group of a 3-amino-2-thiophenecarboxylic acid ester 13can be protected such as by the addition of Boc₂O in a suitable solventsuch as CH₂Cl₂and DMAP. The ester is removed such as with base to formthe free acid 14. The thiophene amide 15 is formed from the acid 14 suchas by coupling with a substituted amine in the presence of DIEA, EDC andHOBt. The 2-protected-amino-thiophene amide 15 is deprotected, such aswith 25% TFA/CH₂Cl₂. The free amine is alkylated such as with asubstituted carboxaldehyde or similar active carbonyl compound, in thepresence of a reducing agent NaCNBH₃ and the like, to form compounds 16.

[0945] Substituted pyridines can be prepared such as by the method foundin Scheme 9. 2-Aminonicotinic acid 17 is coupled with a substitutedamine at a suitable temperature, nonprotic solvent such as CH₂Cl₂, suchas with EDC and HOBt, to form the nicotinamide 18. The nicotinamide 18is reductively alkylated such as with 4-pyridinecarboxaldehyde andNaBH(OAc)₃, to yield the 2-substituted amino-pyridyl carboxamides 19.

[0946] Substituted pyridines may be prepared by the method found inScheme 10. 2-Chloro-nicotinic acid 20 is coupled with an amine 21 at asuitable temperature, such as a temperature over about 100° C. to givethe 2-substituted amino-nicotinic acid 22. The 2-substitutedamino-nicotinic acid 22 is reacted with a substituted amine in thepresence of a coupling reagent, such as BOP-Cl and base, such as TEA toform the 2-substituted amino-nicotinamide 19.

[0947] Alternatively, 2-chloro-nicotinoyl chloride (LG is Cl) is coupledfirst with R¹—NH₂ such as in the presence of base, e.g., NaHCO₃, in asuitable solvent, such as CH₂Cl₂, to form the amide 20A, then couplingwith a pyridylmethylamine to yield the 2-substituted amino-nicotinamide19.

[0948] Imino-substituted pyridines may be prepared by the method foundin Scheme 11. (2-Amino-(4-pyridyl))-carboxamide 23 is reacted with4-pyridine-carboxaldehyde, such as in the presence of p-toluenesulfonicacid monohydrate to yield the imino compound 24.

[0949] Substituted pyridines alternatively may be prepared by the methodfound in Scheme 12. The imino compound 24 is reduced, such as withNaBH₄, to form the substituted amine 25.

[0950] Substituted pyridines can be prepared by the process outlined inScheme 13. A solution of sodium hypobromide is freshly prepared andadded to 2-hydroxynicotinic acid 26 and heated, preferably at atemperature at about 50° C. Additional sodium hypobromide may be neededto form the bromo compound 27. The 5-bromo-2-hydroxynicotinic acid 27 isreacted with thionyl chloride, preferably at a temperature >RT, morepreferably at about 80° C. to form the 2-chloro-nicotinic acid analog28. The acid is coupled with an amine, preferably in the presence ofEDC, HOBT, and DIEA to form the corresponding substituted amide 29.Suzuki coupling with the bromo amide and suitable boronic acids,provides the substituted nicotinamide 30. 2-Amino-nicotinamides 31 areprepared from the corresponding chloro compounds 30 such as by reactingwith substituted amines at a suitable temperature, such as about 80° C.

[0951] Sulfonamides 32 can be prepared from amines 6 as shown in Scheme14. Substituted sulfonyl compounds, such as sulfonyl halides, preferablychloro or bromo, sulfonic acids, an activated ester or reactiveanhydride, or in the form of a cyclic amide, and the like, are added tothe amine 6 to give the sulfonamide compounds 32.

[0952] The reaction is carried out in a suitable solvent, such asCH₂Cl₂, at a temperature between about RT to about the refluxtemperature of the solvent, in the presence of a suitable base, such asDIEA or DMAP.

[0953] The amino group of compounds 6 is preferably in free form,especially when the sulfonyl group reacting therewith is present inreactive form. The amino group may, however, itself be a derivative, forexample by reaction with a phosphite, such as diethylchlorophosphite,1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite. A derivative of such acompound having an amino group also can be a carbamic acid halide or anisocyanate.

[0954] The condensation of activated sulfonic esters, reactiveanhydrides or reactive cyclic amides with the corresponding amines iscustomarily carried out in the presence of an inorganic base, such as analkaline metal hydrogen carbonate of carbonate, or especially an organicbase, for example simple lower (alkyl)₃-amines, for example TEA ortributylamine, or one of the above-mentioned organic bases. If desired,a condensation agent is additionally used, for example as described forfree carboxylic acids.

[0955] The condensation is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or DMF, a halogenatedhydrocarbon, for example CH₂Cl₂, CCl₄ or chlorobenzene, a ketone, forexample acetone, a cyclic ether, for example THF or dioxane, an ester,for example EtOAc, or a nitrile, for example CH₃CN, or in a mixturethereof, as appropriate at reduced or elevated temperature, for examplein a temperature range of from about −40° C. to about +100° C.,preferably from about −10° C. to about 70° C., and when arylsulfonylesters are used, also at temperatures of from about 10-30° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0956] Alcoholic solvents, for example EtOH, or aromatic solvents, forexample benzene or toluene, may also be used. When alkali metalhydroxides are present as bases, acetone may also be added whereappropriate.

[0957] Substituted pyridines can be prepared by the process outlined inScheme 15. 2-Chloronicotinic acid 33 and substituted amine are coupledunder conditions similar to that described in the previous schemes togive the amide 34. 6-Chloro-2-aminopyridines 35 are prepared from theamide 34, such as by reacting with substituted amines at a suitabletemperature, such as above about 80° C., preferably above about 100° C.,more preferably at about 130° C., neat. 6-Chloro-2-aminopyridines 35 arede-chlorinated such as by hydrogenation, for example by treatment withH₂ in the presence of Pd/C, to yield other compounds of the presentinvention 36.

[0958] 1,2,3,6-Tetrahydro-pyridyl substituted anilines are prepared suchas by the procedure described in Scheme 16 (where R^(x) is a substituentselected from those available for substituted R¹). Nitrobenzenes 37 arebrominated, such as with bromine in the presence of acid, H₂SO₄ forexample, or with NBS to yield the 3-bromo derivative 38. Suzuki couplingof the bromo-derivative 38 and a substituted pyridylboronic acid, in anappropriate solvent such as toluene, such as at a temperature above RT,preferably above about 50° C., and more preferably at about 80° C.,yields the pyridyl derivative 39. Alkylation of the nitrophenyl-pyridine39, such as by treatment with iodomethane, preferably above about 50°C., and more preferably at about 80° C., yields the pyridinium compound40, which upon reduction, such as by NaBH₄, yields thetetrahydyropyridine 41.

[0959] 6-Amino substituted pyridines are prepared such as by theprocedure described in Scheme 17. Similar to the method of Scheme 13,chloropyridine 42 and is reacted with an amine, preferably above about50° C., and more preferably at 10 about 80° C., to yield the6-aminopyridines 43.

[0960] A series of substituted anilines are prepared such as by theprocedure described in Scheme 18. A nitrobenzyl bromide 44 is coupledwith morpholine, such as at a temperature at about RT, to yield theheterocyclylmethyl nitrobenzene derivative. Reduction of the nitrocompound, such as with iron powder, preferably above about 50° C., andmore preferably at about 80° C., yields the heterocyclylmethylsubstituted aniline 45.

[0961] Protected alkylamine substituted anilines can be prepared fromthe nitro free amines 46, such as with standard protecting agents andchemistry known in the art, such as BOC chemistry. Reduction of theprotected nitro compound, such as with iron powder, preferably aboveabout 50° C., and more preferably at about 80° C., yields the aniline47.

[0962] Sulfonamide substituted anilines can be prepared fromnitrobezenesulfonyl chlorides 48. Coupling of nitrobezenesulfonylchlorides 48 with reactive heterocyclic compounds, such as substitutedpiperazines, piperidines, and the like, in a protic solvent such asEtOH, such as at a temperature about RT, yields thenitrobezenesulfonamides 48. Reduction of the nitro benzenesulfonamide,such as with iron powder, preferably above about 50° C., and morepreferably at about 80° C., yields the aniline 49.

[0963] A series of perhaloalkyl-substituted anilines 52, where R^(y)represents perhaloalkyl radicals, are prepared such as by the proceduredescribed in Scheme 19. 1-Nitro-4-(perfluoroethyl)benzene can besynthesized by the method described in the reference [John N. Freskos,Synthetic Communications, 18(9), 965-972 (1988)]. Alternatively,1-Nitro-4-(perfluoroalkyl)benzene can be synthesized from the nitrocompound, where X^(a) is a leaving group, such as iodo, by the methoddescribed by W. A. Gregory, et al. [J. Med. Chem., 1990, 33, 2569-2578].

[0964] Reduction of the nitrobenzenes 51, such as with iron powder, at atemperature above about 50° C., and preferably at about 80° C., yieldsthe aniline 52. Hydrogenation, such as with H₂ in the presence ofcatalyst, such as Pd/C, is also possible.

[0965] Additional series of substituted anilines are prepared such as bythe procedures described in Scheme 20 (where R^(x) is a substituentselected from those available for substituted R¹). 2-Alkoxy substitutedanilines 55 are prepared from the corresponding phenol compounds 53 suchas by the Mitsunobu reaction, including treatment with aN,N-dialkylethanolamine and PPh₃ and DEAD to give the correspondingnitro compound 54, followed by hydrogenation, such as with H₂ to givethe aniline 55.

[0966] Alternatively, piperazinyl substituted anilines 58 can beprepared by the treatment of an aniline 56 with anN-substituted-bis(2-chloroethyl)amine, base, such as K₂CO₃ and NaI, at atemperature above about 50° C., preferably above about 100° C., and morepreferably at about 170° C., to give the piperazinylbenzene compound 57.Nitration, such as with H₂SO₄ and HNO₃, at a temperature above 0° C.,and preferably at about RT, followed by hydrogenation, such as with H₂atmosphere gives the substituted aniline 58.

[0967] Alternatively, piperazinyl substituted anilines 61 can beprepared by the treatment of a fluoro-nitro-substituted aryl compounds59. The fluoro-nitro-substituted aryl compounds 59 and 1-substitutedpiperazines are heated, preferably neat, at a temperature above about50° C., and preferably at about 90° C., to yield thepiperazinyl-nitroaryl compounds 60. Hydrogenation, such as with H₂atmosphere in the presence of a catalyst, such as 10% Pd/C, gives thesubstituted aniline 61.

[0968] Substituted indolines are prepared such as by the proceduresdescribed in Scheme 21. Substituted amino-indolines 64 are prepared fromthe nitroindoline 62 and a ketone in the presence of NaHB(OAc)₃ to formthe 1-substituted indoline 63. The nitroindoline 63 is hydrogenated,such as with H₂ in the presence of a catalyst, such as Pd/C, to yieldthe amino-indoline 64.

[0969] Alternatively, substituted amino-indolines 67 are prepared fromthe nitroindoline 62. Nitroindoline 62, is reacted with an acid chlorideto form an amide. Further treatment with a primary or secondary amine,preferably a secondary amine, such as in the presence of NaI, at atemperature above about 50° C., and preferably at about 70° C. yieldsthe nitroindoline 65. The nitro compound 65 is hydrogenated, such aswith H₂ in the presence of a catalyst, such as Pd/C, to yield theamino-indoline 66. The carbonyl is reduced, such as with BH₃-THF yields1-aminoalkyl-indolines 67.

[0970] Substituted indolines are prepared such as by the proceduresdescribed in Scheme 22. Substituted acetamides 69 are prepared from theacylation of halo-5-nitroanilines 68 (where LG is bromo or chloro,preferably chloro) with an acylating agent, such as acetyl chloride oracetic anhydride, under standard coupling chemistry, such as with DIEA,and DMAP, at a temperature of about RT, in a suitable solvent, such asCH₂Cl₂, DMF and/or DMAC. The N-(2-methylprop-2-enyl)acetamide 70 isprepared from the acetamide 69, such as by the treatment of base, suchas NaH in anhydrous DMF and a 3-halo-2-methylpropene such as3-bromo-2-methylpropene or 3-chloro-2-methylpropene, at a temperaturebetween about 0° C. and RT, and preferably at about RT; or with CsCO₃ ata temperature above RT, preferably above about 50° C. and morepreferably above about 60° C. Cyclization of theN-(2-methylprop-2-enyl)acetamide 70, such as by the Heck-type reaction(treatment with Pd(OAc)₂ in the presence of base, for exampletetraethyl-ammonium chloride, sodium formate, and NaOAc) at atemperature above about 50° C., and preferably at about 80° C., yieldsthe protected (3,3-dimethyl-2,3-dihydro-indol-1-yl)ethanone 71.Deprotection, such as with strong acid such as AcOH on HCl at atemperature above about 50° C., and preferably at about 70-80° C.,yields the 3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl 72.Alternatively, the protected dihydro-6-nitro indoline 71 can be reduced,such as with Fe, or with 10% Pd/C in the presence of an excess ofNH₄CO₂H, or with H₂ in the presence of a catalyst to form the protecteddihydro-6-amino indoline 71a.

[0971] Substituted anilines are prepared such as by the proceduresdescribed in Scheme 23. Nitrophenyl esters 74 are formed from the acid73, such as by treatment with MeOH and acid. Alkylation of the ester 74,such as by treatment with base, followed by alkyl halide, yields thebranched alkyl compounds 75. Reduction of the ester 75, such as withBH₃, yields the alcohol 76. The aldehyde 77 is prepared from the alcohol76, such as by treatment with TPAP in the presence ofN-methylmorpholine-N-oxide. Subsequent treatment withmethoxymethyltriphenylphosphonium chloride and KHMDS yields 77. Couplingof the aldehyde 77 with morpholine, such as with NaBH(OAc)₃ yields thetertiary amine 78. Reduction of the nitro compound, such as with acid,for example AcOH, and zinc yields the aniline 79.

[0972] Substituted aminomethyl compounds are prepared such as by theprocedure described in Scheme 24. A piperidinemethanol 80 is reactedwith formaldehyde and NaCNBH₃. Subsequently, base, such as sodiumhydride, and a halo substituted cyclic nitrile gives the ether 81.Hydrogenation of 81 under conditions described above, furnishes theaminomethyl compound 82.

[0973] Substituted aniline compounds are prepared such as by theprocedure described in Scheme 25 (where R^(x) is a substituent selectedfrom those available for substituted R¹, preferably haloalkyl or alkyl).Alkynyl-aniline 84, prepared similar to that described in Scheme 46, ishydrogenated such as with H₂ in the presence of a catalyst, such asPd(OH)₂, to yield the substituted alkyl 85.

[0974] Substituted bromophenyl compounds are prepared such as by theprocedure described in Scheme 26. Bromine is added to a optionallysubstituted nitrobenzene 86, silver(II)sulfate and acid, such as H₂SO₄,to provide the bromo derivative 87.

[0975] Substituted anilines are prepared such as by the proceduredescribed in Scheme 27 (where R^(t) and R^(v) are alkyl, or togetherwith the nitrogen atom form a 4-6 membered heterocyclic ring). Acryloylchloride 88 is reacted with an amine, preferably a secondary amine, suchas at a temperature between about 0° C. and about RT, to form the amide89. A bromo-nitrobenzene 87 is reacted with the amide 89, such as in thepresence of base, for example TEA, together with Pd(OAc)₂ and Pd(PPh₃)₄,at a temperature above about 50° C., and preferably at about 120° C.,such as in a sealed container, to form the substituted alkene 90.Hydrogenation of the alkene 90, such as with H₂-in the presence of acatalyst, for example Pd/C catalyst yields the substituted aniline 91.Reduction of the amide 91, such as with LiAlH₄, at a temperature aboveabout 50° C., and preferably at about 80° C. yields the aniline 92.

[0976] Substituted indoles are prepared such as by the proceduredescribed in Scheme 28. A nitroindole 93 is coupled with a halocompound, in the presence of base, for example K₂CO₃. Heating at atemperature above about 50° C., and preferably at about reflux yieldsthe substituted-nitro-1H-indole 94. Hydrogenation similar to conditionsdescribed above yield the amino derivative 95.

[0977] Substituted pyrimidines are prepared such as by the proceduredescribed in Scheme 29. 2-Methylthio-5-pyrimidyl acids 98 are preparedfrom the corresponding esters 96 similar to procedures described above.The amides 99 are formed from the acids 98 by coupling with the aminesuch as in the presence of HATU and base, TEA for example. Themethylthio group can be removed, such as with Raney-Ni and heat,preferably at about reflux temperature, to form the pyrimidine 100.

[0978] Substituted aminomethyl compounds are prepared such as by theprocedure described in Scheme 30 (where LG is a leaving group, such asCl). Strong base, such as NaH is added to an alcohol and heated at about50° C. to form the sodium alkoxide, which is added to a halo compound,such as 2-chloro-4-cyanopyridine and heated at a temperature above about50° C., and preferably at about 70° C. to form the ether 102.Hydrogenation yields the aminomethyl derivative 103.

[0979] Substituted anilines are prepared such as by the proceduredescribed in Scheme 31. Treatment with the haloalkyl alcohol 104 with analcohol, such as in the presence of DEAD and PPh₃ yields the ether 105or 106.

[0980] Functionalized pyridines are prepared such as by the proceduredescribed in Scheme 32. 2-Fluoropyridine 107 is treated with base, suchas LDA at a temperature below about 0° C., and preferably at about −78°C., and quenched with a stream of dry CO₂ to form the nicotinic acid108. Alternatively, solid CO₂ (dry ice) can be used, preferably driedwith N₂ prior to use. The acid 108 is converted to the acid halide 109,such as by treatment with thionyl chloride and heating at a temperatureabove about 50° C., and preferably at about reflux.

[0981] Chloro-substituted pyridines 110 are prepared such as by theprocedure described in Scheme 33. 2-Chloronicotinic acid is activatedwith ethyl chloroformate, in the presence of base, such as TEA, at atemperature of about RT. Reaction with an amine produces amide 110.Alternatively, the amine can be coupled with the acid chloride 111, suchas with polymer-supported DIPEA, to form amide 110. Excess acid chlorideis removed by treating the reaction mixture with polymer-supportedtrisamine resin.

[0982] Amino-substituted indoles 110 are prepared such as by theprocedure described in Scheme 34. Nitroindoline 112 is reacted withN-methyl-4-piperidone in the presence of NaOMe at a temperature aboveabout 50° C., and preferably at about reflux, to form the 3-substitutedindole 113. Hydrogenation as previously discussed yields the aminoindole 114.

[0983] Alkylated indazoles can be prepared by the process outlined inScheme 35. To a solution of 6-nitroindazole 115 in a solvent such as THFis added strong base, such as NaH at a temperature below RT, preferablyat about 0° C. Alkylhalides, such as where R″ is methyl, are added andreacted at a temperature about RT to give 1-alkyl-6-nitro-1H-indazole116. The nitro indazole 116 is hydrogenated, such as with an H₂atmosphere in the presence of a catalyst, such as Pd/C to give the1-substituted-6-amino-1H-indazole 117.

[0984] Brominated indazoles can be prepared by the process outlined inScheme 36. NBS is slowly added to an acidic solution, such as a mixtureof TFA:H₂SO₄ (5:1) and tert-butyl-4-nitrobenzene 118 at a temperature ofabout RT to yield the brominated compound 119.

[0985] Substituted anilines can be prepared by the process outlined inScheme 38. A mixture of 1-(substituted)-2-bromo-4-nitrobenzene 120(where R^(x) is a substituent selected from those available forsubstituted R¹) and N-methylpiperazine is heated, such as with orwithout solvent, preferably without solvent, at a temperature above RT,preferably at a temperature above about 100° C., and more preferably ata temperature at about 130° C. to give the1-[5-(substituted)-2-nitrophenyl]-4-methylpiperazine 121. The nitrocompound 121 is hydrogenated, such as with an H₂ atmosphere in thepresence of a catalyst, such as Pd/C to furnish4-(substituted)-2-(4-methylpiperazinyl)phenylamine 122.

[0986] Tricyclic heterocycles can be prepared by the process outlined inScheme 38. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 123 is heated inPOCl₃ at a temperature above RT, preferably at a temperature sufficientfor reflux, to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 124.The 1-chloro-7-nitro-3,4-dihydroisoquinoline 124 is dissolved in asolvent, such as THF, and H₂NNH₂ is added. The reaction is evaporated toa residue, then heated with HC(OEt)₃ at a temperature above RT,preferably at a temperature above about 75° C., and more preferably at atemperature at about 115° C. to give the nitro-substituted tricyclic.Hydrogenation, such as with an H₂ atmosphere in the presence of acatalyst, such as Pd/C, gives2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 125.

[0987] Indazolyl ethers can be prepared by the process outlined inScheme 39. 6-Nitro-1H-2-hydroindazol-3-one 126 is protected such as withBoc₂O and DMAP in CH₂Cl₂ at a temperature of about RT, to give theprotected 6-nitro-2-hydroindazol-3-one. The protected6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where R^(x) isan appropriate substituent selected from the possible substituents on R)and Ph₃P in a solvent, such as THF, and DEAD, at a temperature of aboutRT, to give the protected 6-nitro(indazol-3-yl) ether. The nitrointermediate is hydrogenated, such as with an H₂ atmosphere in thepresence of a catalyst, such as Pd/C, to give the protected6-amino(indazol-3-yl) ether 127. The amine 127 is coupled and2-chloronicotinic acid in a solvent, such as an alcohol, preferablypentanol, at a temperature above RT, preferably at a temperature aboveabout 75° C., and more preferably at a temperature at about 130° C. togive the coupled and deprotected compound 128.

[0988] Indolinyl substituted carboxamides can be prepared from thecorresponding nitro indoline 129 by the process outlined in Scheme 40.For example, 3,3-dimethyl-6-nitroindoline 129 is alkylated, such as withN-protected-4-formylpiperidine in the presence of NaHB(OAc)₃ and acid,such as glacial AcOH, and solvent, such as dichloromethane, at atemperature of about RT, to afford the alkylated indane 130.Hydrogenation of the alkylated indane 130, such as with an H₂ atmospherein the presence of a catalyst, such as Pd/C, in the presence of asolvent, such as an alcohol, preferably MeOH, to give the aminointermediate 131. Alternatively, other hydrogenation methods can beused, such as Fe powder with NH₄Cl. Coupling of the amine 131, such aswith 2-chloronicotinic acid and DIEA, HOBt and EDC, in a solvent such asCH₂Cl₂ at a temperature of about RT provides the protected carboxamide132, which upon deprotection and alkylation yields other compounds ofthe invention, 133 and 134, respectively. Alternatively, amine 131 isreacted with 2-fluoronicotinoyl chloride to form a 2-fluoronicotinamide,which can be alkylated, such as in Scheme 10.

[0989] Substituted anilines can be prepared by the process outlined inScheme 41. 1-Methyl-4-piperidinone 135 is added to a solution of strongbase such as LIHMDS, in a solvent such as THF, at a temperature belowRT, preferably lower than about −50° C., more preferably at about −78°C. Tf₂NPh is reacted with the enolate at a temperature of about RT, togive 1-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl)sulfonate.A mixture of the triflate intermediate, bis(pinacolato)diboron,potassium acetate, PdCl₂dppf, and dppf in a solvent such as dioxane isheated at a temperature above RT, preferably at a temperature aboveabout 50° C., and more preferably at a temperature at about 80° C. togive4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane136. The substituted aniline 137 is formed from the 1,3,2-dioxaborolane136 such as with treatment with an amine in the presence of1,1′-bis(diphenyphosphino)ferrocene-palladium dichloride and base, suchas K₂CO₃, in a solvent such as DMF at a temperature above RT, preferablyat a temperature above about 50° C., and more preferably at atemperature at about 80° C.

[0990] Substituted anilines can be prepared by the process outlined inScheme 42. 4-Cyano-4-phenylpiperidine hydrochloride 138 is treated withbase, such as KOH, at a temperature above RT, preferably at atemperature above about 100° C., and more preferably at a temperature atabout 160° C., to provide the phenyl piperidine 139. Alkylation of thephenyl piperidine 139, such as with formaldehyde and NaCNBH₃ in asolvent such as CH₃CN, with sufficient acid to maintain the reaction pHnear 7, to provide the alkylated piperidine 140. Nitration of thephenylpiperidine 140, such as with H₂SO₄ and fuming HNO₃ at atemperature below RT, and preferably at about 0° C., gives the nitrointermediate 141. Hydrogenation of the nitro intermediate 141, such aswith an H₂ atmosphere in the presence of a catalyst, such as Pd/C, inthe presence of a solvent, such as an alcohol, preferably MeOH, to givethe amino intermediate 142.

[0991] Substituted amides can be prepared by the process outlined inScheme 43. 3-Nitrocinnamic acid 143 is coupled with 1-methylpiperazinein the presence of EDC and a solvent such as CH₂Cl₂, at a temperature ofabout RT gives the carboxamide 144.

[0992] Substituted benzylamines can be prepared by the process outlinedin Scheme 44. A substituted bromobenzylamine 145 where R^(1a) is asubstituent described for R¹ is protected such as with Boc₂O in thepresence of base, such as TEA in an appropriate solvent such as CH₂Cl₂.The protected bromobenzylamine 146 is alkylated, such as with1-dimethylamino-2-propyne in the presence of catalyst, such asPdCl₂(PPh₃)₂, and CuI, in the presence of base, such as TEA, at atemperature above RT, preferably at a temperature above about 50° C.,and more preferably at a temperature at about 100° C., such as in asealed tube, to form the propynylbenzylamine 147. Thepropynylbenzylamine is hydrogenated such as with H₂ in the presence ofPd(OH)₂ and MeOH to provide the propylbenzylamine 148. Deprotection,such as with strong acid, such as TFA, for removal of a Boc protectinggroup, yields the propylbenzylamine 149.

[0993] Substituted benzylamines can be prepared by the process outlinedin Scheme 45. The protected bromobenzylamine 146 is alkylated, such aswith propargyl alcohol in the presence of catalyst, such as PdCl₂(PPh₃),and CuI, in the presence of base, such as TEA, at a temperature aboveRT, preferably at a temperature above about 50° C., and more preferablyat a temperature at about 100° C., such as in a sealed tube, to form theprotected hydroxypropynylbenzylamine 150. The protectedhydroxypropynylbenzylamine is treated with N-methylmorpholine oxide inthe presence of a catalyst, such as tetrapropylammonium perruthenate, toform the aldehyde intermediate. Reductive amination, such as with theaddition of morpholine and NaBH(OAc)₃ provides the morpholinylderivative. Deprotection, such as with strong acid, such as TFA, forremoval of a Boc protecting group, yields the propylbenzylamine 151.

[0994] Substituted aminomethyl compounds are prepared such as by theprocedure described in Scheme 46. A halo compound 152, is reacted withan alkyne in the presence of PdCl₂(PPh₃)₂ and CuI, with base is heatedat a temperature above about 50° C., and preferably at about 100° C.,such as in a sealed container, to provide the substituted alkyne 153.

[0995] Substituted heterocycles may be prepared by the method found inScheme 47. Chloro-heterocycles 154 (where LG is OH) is coupled with anamine 155 at a suitable temperature, such as a temperature over about100° C. to give the 2-substituted amino-nicotinic acid 156. The2-substituted amino-nicotinic acid 156 is reacted with a substitutedamine in the presence of a coupling reagent, such as BOP-Cl and base,such as TEA to form the 2-substituted amino-nicotinamide 157.

[0996] Alternatively, 2-chloro-nicotinoyl chloride 154 (where LG is Cl)is coupled first with R²—NH₂, such as in the presence of base, e.g.,NaHCO₃, in a suitable solvent, such as IpOH or CH₂Cl₂, to form the amide158, then coupled with an amine 155 to yield the 2-substitutedamino-nicotinamide 157. Where A is a pi-electron rich heterocycle, theaddition of KF, such as 40% KF on alumina in IpOH, at a temperature overabout 100° C., preferably about 160° C., can be used in the formation of157 from 158.

[0997] 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine may beprepared by the method found in Scheme 48. Nitrobenzylpyridines 159 arealkylated, such as with MeI, in the presence of TBAI and base to formthe pyridinium compound 160. The pyridinium compounds 160 arehalogenated, such as brominated with NBS, to form the brominatedpyridinium compounds 161 which are reduced such as with NaBH₄ to formthe tetrahydro-pyridines 162. Palladium catalyzed intramolecular Heckcoupling followed by hydrogenation forms the hexahydro-fluorenes 164.

[0998] The starting compounds defined in Schemes 1-48 may also bepresent with functional groups in protected form if necessary and/or inthe form of salts, provided a salt-forming group is present and thereaction in salt form is possible. If so desired, one compound offormulas I-XII can be converted into another compound of formulas I-XIIor a N-oxide thereof; a compound of formulas I-XII can be converted intoa salt; a salt of a compound of formulas I-XII can be converted into thefree compound or another salt; and/or a mixture of isomeric compounds offormulas I-XII can be separated into the individual isomers.

[0999] N-Oxides can be obtained in a known matter by reacting a compoundof formulas I-XII with hydrogen peroxide or a peracid, e.g.3-chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane,at a temperature between about −10-35° C., such as about 0° C.—RT.

[1000] If one or more other functional groups, for example carboxy,hydroxy, amino, or mercapto, are or need to be protected in a compoundof formulas I-XII or in the synthesis of a compound of formulas I-XII,because they should not take part in the reaction, these are such groupsas are usually used in the synthesis of peptide compounds, and also ofcephalosporins and penicillins, as well as nucleic acid derivatives andsugars.

[1001] The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned above and hereinafter.

[1002] The protection of such functional groups by such protectinggroups, the protecting groups themselves, and their removal reactionsare described for example in standard reference works, such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,in “Methoden der organischen Chemie” (Methods of organic chemistry),Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart1974, in H.-D. Jakubke and H. Jescheit, “Aminosäuren, Peptide, Proteine”(Amino acids, peptides, proteins), Verlag Chemie, Weinheim, DeerfieldBeach, and Basel 1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate:Monosaccharide und Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

[1003] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more of the protecting groups mentioned aboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

[1004] Salts of a compound of formulas I-XII with a salt-forming groupmay be prepared in a manner known per se. Acid addition salts ofcompounds of formulas I-XII may thus be obtained by treatment with anacid or with a suitable anion exchange reagent. A salt with two acidmolecules (for example a dihalogenide of a compound of formulas I-XII)may also be converted into a salt with one acid molecule per compound(for example a monohalogenide); this may be done by heating to a melt,or for example by heating as a solid under a high vacuum at elevatedtemperature, for example from about 130° C. to about 170° C., onemolecule of the acid being expelled per molecule of a compound offormulas I-XII.

[1005] Salts can usually be converted to free compounds, e.g. bytreating with suitable basic agents, for example with alkali metalcarbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide.

[1006] A compound of formulas I-XII, wherein Z is oxygen, can beconverted into the respective compound wherein Z is sulfur, for example,by using an appropriate sulfur compound, e. g. using reaction withLawesson's reagent(2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)in a halogenated hydrocarbon, such as CH₂Cl₂, or an aprotic solvent,such as toluene or xylene, at temperatures from about 30° C. to reflux.

[1007] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H+ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about −100° C. to about 190° C.,preferably from about −80° C. to about 150° C., for example at about −80to about 60° C., at RT, at about −20 to about 40° C. or at the boilingpoint of the solvent used, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under argon or nitrogen.

[1008] Salts may be present in all starting compounds and transients, ifthese contain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

[1009] In certain cases, typically in hydrogenation processes, it ispossible to achieve stereoselective reactions, allowing for exampleeasier recovery of individual isomers.

[1010] The solvents from which those can be selected which are suitablefor the reaction in question include for example water, esters,typically lower alkyl-lower alkanoates, e.g., ethyl acetate, ethers,typically aliphatic ethers, e.g., diethylether, or cyclic ethers, e.g.,THF, liquid aromatic hydrocarbons, typically benzene or toluene,alcohols, typically MeOH, EtOH or 1-propanol, IPOH, nitriles, typicallyCH₃CN, halogenated hydrocarbons, typically CH₂Cl₂, acid amides,typically DMF, bases, typically heterocyclic nitrogen bases, e.g.pyridine, carboxylic acids, typically lower alkanecarboxylic acids,e.g., AcOH, carboxylic acid anhydrides, typically lower alkane acidanhydrides, e.g., acetic anhydride, cyclic, linear, or branchedhydrocarbons, typically cyclohexane, hexane, or isopentane, or mixturesof these solvents, e.g., aqueous solutions, unless otherwise stated inthe description of the process. Such solvent mixtures may also be usedin processing, for example in chromatography.

[1011] The invention relates also to those forms of the process in whichone starts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described above as preferred.

[1012] The compounds of formulas I-XII, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

[1013] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[1014] Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art.

[1015] For example, amine 1 can be prepared by reduction of thecorresponding nitro. The reduction preferably takes place in thepresence of a suitable reducing agent, such as tin(II) chloride orhydrogen in the presence of an appropriate catalyst, such as Raneynickel (then preferably the hydrogen is used under pressure, e.g.between 2 and 20 bar) or PtO₂, in an appropriate solvent, e.g. analcohol, such as MeOH. The reaction temperature is preferably betweenabout 0° C. and about 80° C., especially about 15° C. to about 30° C.

[1016] It would also be possible to reduce the nitro compound afterforming the amide compound under reaction conditions analogous to thosefor the reduction of nitro compounds described above. This wouldeliminate the need to protect the free amino group as described inScheme 1.

[1017] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the examples.

[1018] All remaining starting materials are known, capable of beingprepared according to known processes, or commercially obtainable; inparticular, they can be prepared using processes as described in theexamples.

[1019] Compounds of the present invention can possess, in general, oneor more asymmetric carbon atoms and are thus capable of existing in theform of optical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

[1020] The compounds of this invention may contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,scalemic mixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention.

[1021] The compounds of this invention may also be represented inmultiple tautomeric forms, for example, as illustrated below:

[1022] The invention expressly includes all tautomeric forms of thecompounds described herein.

[1023] The compounds may also occur in cis- or trans- or E- or Z- doublebond isomeric forms. All such isomeric forms of such compounds areexpressly included in the present invention. All crystal forms of thecompounds described herein are expressly included in the presentinvention.

[1024] Substituents on ring moieties (e.g., phenyl, thienyl, etc.) maybe attached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

[1025] The compounds of this invention may contain heterocyclic ringsystems attached to another ring system. Such heterocyclic ring systemsmay be attached through a carbon atom or a heteroatom in the ringsystem.

[1026] Alternatively, a compound of any of the formulas delineatedherein may be synthesized according to any of the processes delineatedherein. In the processes delineated herein, the steps may be performedin an alternate order and may be preceded, or followed, by additionalprotection/deprotection steps as necesssary. The processes may furthercomprise use of appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase,simulated moving bed (“SMB”)), extraction, distillation, trituration,reverse phase HPLC and the like. Reactions conditions such astemperature, duration, pressure, and atmosphere (inert gas, ambient) areknown in the art and may be adjusted as appropriate for the reaction.

[1027] As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) Ed. (2001); M.Bodanszky, A. Bodanszky: The practice of Peptide SynthesisSpringer-Verlag, Berlin Heidelberg 1984; J. Seyden-Penne: Reductions bythe Alumino- and Borohydrides in Organic Synthesis, 2^(nd) Ed.,Wiley-VCH, 1997; and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

[1028] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[1029] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-XII. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention.

[1030] Unless otherwise noted, all materials were obtained fromcommercial suppliers and used without further purification. Anhydroussolvents such as DMF, THF, CH₂Cl₂ and toluene were obtained from theAldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under a nitrogen atmosphere.Flash chromatography was performed using Aldrich Chemical Company silicagel (200-400 mesh, 60A) or Biotage pre-packed column. Thin-layerchromatography (TLC) was performed with Analtech gel TLC plates (250μ).Preparative TLC was performed with Analtech silica gel plates(1000-2000μ). Preparative HPLC was conducted on Beckman or Waters HPLCsystem with 0.1% TFA/H₂O and 0.1% TFA/CH₃CN as mobile phase. The flowrate was at 20 ml/min. and gradient method was used. ¹H NMR spectra weredetermined with super conducting FT NMR spectrometers operating at 400MHz or a Varian 300 MHz instrument. Chemical shifts are expressed in ppmdownfield from internal standard tetramethylsilane. All compounds showedNMR spectra consistent with their assigned structures. Mass spectra (MS)were determined on a Perkin Elmer—SCIEX API 165 electrospray massspectrometer (positive and, or negative) or an HP 1100 MSD LC-MS witheletrospray ionization and quadrupole detection. All parts are by weightand temperatures are in Degrees centigrade unless otherwise indicated.

[1031] The following abbreviations are used: AIBN -2,2′-azobisisobutyronitrile Ar - argon AgSO₄ - silver sulfate ATP -adenosine triphosphate BH₃ - borane Boc - tert-butyloxycarbonyl Boc₂O -Boc anhydride BOP—Cl - bis (2-oxo-3-oxazolidinyl)phosphinic chlorideBr₂- bromine BSA - bovine serum albumin t-BuOH - tert-butanol CAN -ammonium cerium (IV) nitrate CH₃CN, AcCN - acetonitrile CH₂Cl₂ -dichloromethane CH₃I, MeI - iodomethane, methyl iodide CCl₄ - carbontetrachloride CCl₃ - chloroform CO₂ ₋ carbon dioxide Cs₂CO₃ - cesiumcarbonate DIEA - diisopropylethylamine CuI - copper iodide DCE -1,2-dichloroethane DEAD - diethyl azodicarboxylate DIEA -diisopropylethylamine dppf - 1,1-diphenylphosphinoferrocene DMAP -4-(dimethylamino)pyridine DMAC - N,N-dimethylacetamide DMF -dimethylformamide DMSO - dimethylsulfoxide DTT - dithiothreitol EDC,EDAC - 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochlorideEGTA - ethylene glycol-bis(β-aminoethyl ether)- N,N,N′,N′-tetraaceticacid EtOAc - ethyl acetate EtOH - ethanol Et₂O - diethyl ether Fe - irong - gram h - hour HATU - O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate H₂ - hydrogen H₂O - water HCl -hydrochloric acid H₂SO₄ ₋ sulfuric acid H₂NNH₂ ₋ hydrazine HC(OEt)₃ -triethylorthoformate HCHO, H₂CO - formaldehyde HCO₂Na - sodium formateHOAc, AcOH - acetic acid HOAt - 1-hydroxy-7-azabenzotriazole HOBt -hydroxybenzotriazole IpOH - isopropanol K₂CO₃ - potassium carbonateKHMDS - potassium hexamethylsilazane KNO₃ - potassium nitrate KOAc -potassium acetate KOH - potassium hydroxide LAH, LiAlH₄ - lithiumaluminum hydride LDA - lithium diisopropylamide LiCl - lithium chlorideLiHMDS - lithium hexamethyldisilazide MeOH - methanol MgCl₂ - magnesiumchloride MgSO₄ - magnesium sulfate mg - milligram ml - milliliterMnCl₂ - manganese chloride NBS - N-bromosuccinimide NMO -4-methylmorpholine, N-oxide NMP - N-methylpyrrolidone Na₂SO₄ - sodiumsulfate Na₂S₂O₅ - sodium metabisulfite NaHCO₃ - sodium bicarbonateNa₂CO₃ - sodium carbonate NaCl - sodium chloride NaH - sodium hydrideNaI - sodium iodide NaOH - sodium hydroxide NaOMe - sodium methoxideNaCNBH₃ - sodium cyanoborohydride NaBH₄ - sodium borohydride NaNO₂ -sodium nitrate NaBH(OAc)₃ - sodium triacetoxyborohydride NH₄Cl -ammonium chloride N₂ - nitrogen Pd/C - palladium on carbon PdCl₂(PPh₃)₂ - palladium chloride bis(triphenylphosphine) PdCl₂ (dppf) -1,1-bis (diphenylphosphino) ferrocene palladium chloride Pd(PPh₃)₄ -palladium tetrakis triphenylphosphine Pd(OH)₂ - palladium hydroxidePd(OAc)₂ - palladium acetate PMB - para methoxybenzyl POCl₃ - phosphorusoxychloride PPh₃ - triphenylphosphine PtO₂ - platinum oxide RT - roomtemperature SiO₂ - silica SOCl₂ - thionyl chloride TBAI -tetrabutylammonium iodide TEA - triethylamine Tf₂NPh -N-phenyltrifluoromethanesulfonimide TFA - trifluoroacetic acid THF -tetrahydrofuran TPAP - tetrapropylammoniumperruthenate Tris-HCl - Tris(hydroxymethyl) aminomethane hydrochloride salt Zn - zinc

Preparation I—3-nitro-5-trifluoromethyl-phenol

[1032] 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g, Aldrich) andpyridine-HCl (41.8 g, Aldrich) were mixed together and heated neat at210° C. in an open flask. After 2.5 h the mixture was cooled to RT andpartitioned between 1N HCl and EtOAc. The EtOAc fraction was washed with1N HCl (4×), brine (1×), dried with Na₂SO₄, filtered and concentrated invacuo to form 3-nitro-5-trifluoromethyl-phenol as an off-white solid.

Preparation II—1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine

[1033] 3-Nitro-5-trifluoromethyl-phenol (8.81 g) was dissolved in THF(76 ml). 1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph₃P (11.15 g)were added and the solution was cooled to −20° C. A solution of DEAD(6.8 ml, Aldrich) in THF (36 ml) was added dropwise, maintaining thetemperature between −20 and −10° C. The reaction was warmed to RT andstirred overnight. The reaction was concentrated in vacuo and trituratedwith hexane. The yellow solid was removed by filtration and washed withEt₂O (25 ml), and hexane. The white filtrate was washed with 1N NaOH(2×), brine (1×) and the hexane layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was purified with flashchromatography (SiO₂, 5-10% EtOAc/hexane) to obtain1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.

[1034] The following compounds were prepared similarly to the procedureoutlined above:

[1035] a)(S)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine

[1036] b)(R)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine.

[1037] c) (R)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[1038] d) 4-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-methyl-piperidine.

[1039] e) (S)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[1040] f) 1-Boc-3-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-azetidine.

[1041] g) N-Boc-[2-(5-nitro-2-pentafluoroethyl-phenoxy)-ethyl]amine.

[1042] h) (R) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.

[1043] i) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-azetidine.

[1044] j) (S)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine

[1045] k) (S) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.

[1046] l) (R)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine

Preparation III—1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine

[1047] 1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine (470 mg)was dissolved in MeOH (12 ml) and Pd/C (10 mg) was added. After spargingbriefly with H₂, the mixture was stirred under H₂ for 6 H. The catalystwas removed by filtration and the MeOH solution was concentrated invacuo to yield 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine asan off-white foam.

[1048] The following compounds were prepared similarly to the procedureoutlined above:

[1049] a) 1-Boc-2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

[1050] b)2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-1-methyl-pyrrolidine.

[1051] c) [2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine. ESI(M+H)=222.

[1052] d) [2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-yl]methylamine.

[1053] e) [2-(2-Morpholin-4-yl-propoxy)-pyridin-4-yl]methylamine.

[1054] f) [2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-yl]methylamine.ESI MS: (M+H)=222.

[1055] g) (4-Aminomethyl-pyridin-2-yl)-(3-morpholin-4-yl-propyl)-amine.ESI MS: (M+H)=251.

[1056] h) 4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine.

[1057] i) 4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenylamine.

[1058] j)3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[1059] k)3-(1-Isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[1060] l) (S) 3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.

[1061] m) 3-(2-Pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.

[1062] n) 3-(2-Piperidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.

[1063] o) (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[1064] p) (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[1065] q) (R)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

[1066] r) (S)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine

[1067] s) (R) 3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.

[1068] t) (R)2-(5-Amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-ethanol.

[1069] u) 3-(1-Boc-azetidin-3-ylmethoxy)-4-pentafluoroethyl-phenylamine.

[1070] v) 3-(2-(Boc-amino)ethoxy)-4-pentafluoroethyl-phenylamine.

[1071] w) 6-Amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. M+H 193.2.Calc'd 192.1.

[1072] x) 2,2,4-Trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine.

[1073] y)1-(6-Amino-2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone. M+H221.4. Calc'd 220.3.

[1074] z) [2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-yl]-methylamine.

[1075] aa)[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-yl]-methylamine. M+H236.3. Calc'd 235.2.

[1076] ab) 3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.M+H 360.3.

[1077] ac) 2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine.

[1078] ad) 3-Morpholin-4-ylmethyl-4-pentafluoroethyl-phenylamine.

[1079] ae)3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine. M+H410.3. Calc'd 409.4.

[1080] af)7-Amino-2-(4-methoxy-benzyl)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.M+H 311.1.

[1081] ag) 7-Amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.

[1082] ah)(3-Amino-5-trifluoromethyl-phenyl)-(4-Boc-piperazin-1-yl)-methanone. M+H374.3; Calc'd 373.

[1083] ai) 3-(4-Boc-Piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.

[1084] aj)1-(7-Amino-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone. M+H219.2.

[1085] ak){2-[2-(1-Methylpiperidin-4-yl)ethoxy]-pyridin-4-yl}-methylamine.

[1086] al) {2-[2-(1-Pyrrolidinyl)ethoxy]-pyridin-4-yl}-methylamine.

[1087] am){2-[2-(1-Methylpyrrolin-2-yl)ethoxy]-pyridin-4-yl}-methylamine.

[1088] an) (2-Chloro-pyrimidin-4-yl)-methylamine.

[1089] ao) 3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenylamine.

[1090] ap) 4-tert-Butyl-3-(1-Boc-pyrrolidin-3-ylmethoxy)-phenylamine.M+H 385.

[1091] aq) 4-tert-Butyl-3-(1-Boc-azetidin-3-ylmethoxy)-phenylamine. M+Na357.

[1092] ar) (S)4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenylamine. M+Na 371.

[1093] as) 3-tert-Butyl-4-(4-Boc-piperazin-1-yl)-phenylamine

[1094] at) 3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenylamine.

[1095] au) 3,3-Dimethyl-2,3-dihydro-benzofuran-6-ylamine.

[1096] av)3,9,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine.

[1097] aw) 4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenylaminewas prepared using EtOH as the solvent.

[1098] ax) 4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenylamine.

[1099] ay) (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

[1100] az) (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

PreparationIV—1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

[1101] 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine (4.37 g)was dissolved in CH₂Cl₂ (100 ml) and NaHCO₃ (2.4 g, Baker) was added.2-Fluoropyridine-3-carbonyl chloride (2.12 g) was added an the reactionwas stirred at RT for 2.5 h. The reaction was filtered and concentratedin vacuo to yield a yellow foam. (30%) EtOAc/Hexane was added and1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidineprecipitated as an off white solid.

[1102] The following compounds were prepared similarly to the procedureoutlined above:

[1103] a)2-Fluoro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1104] b)N-[4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-fluoro-nicotinamide.

[1105] c)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.

[1106] d)N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide

[1107] e)N-[3,3-Dimethyl-1-(2-(Boc-amino)acetyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.

[1108] f)N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.M+H 344.5. Calc'd 343.4.

[1109] g)2-Fluoro-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide.M+H 316.2. Calc'd 315.1.

[1110] h)N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.M+H 316.1. Calc'd 315.10.

[1111] i)2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 481. Calc'd 480.

[1112] j)2-Fluoro-N-(2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 400.

[1113] k)2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-nicotinamide.M+H 447.0. Calc'd 446.

[1114] l)2-Fluoro-N-(3-morpholin-4-ylmethyl-4-pentafluoroethyl-phenyl)-nicotinamide.

[1115] m) 2-Fluoro-N-[4-iodophenyl]-nicotinamide.

[1116] n)2-Fluoro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 314.0, Calc'd 311.

[1117] o)2-Fluoro-N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 495.

[1118] p)2-Fluoro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 483.3; Calc'd 482.

[1119] q)N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-fluoro-nicotinamide.M+H 430.0.

[1120] r)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.M+H 383.2; Calc'd 382.5.

[1121] s) N-(4-tert-Butylphenyl)-2-fluoronicotinamide.

[1122] t) N-(4-Trifluoromethylphenyl)-2-fluoronicotinamide.

[1123] u)2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.M-H 468.2; Calc'd 469.16.

[1124] v)2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-4-tert-butyl-phenyl]-nicotinamide.

[1125] w) (S)N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-fluoro-nicotinamide.M+Na 494.

[1126] x)N-[3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-2-fluoro-nicotinamidewas prepared with K₂CO₃. instead of NaHCO₃.

[1127] y) N-(3-Bromo-5-trifluoromethyl-phenyl)-2-fluoro-nicotinamide.

[1128] z)2-Fluoro-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide.

[1129] aa)2-Fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide

[1130] ab)N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.

PreparationV—1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy)-piperidine

[1131]1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidinewas prepared from 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidineand 2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

[1132] The following compounds were prepared similarly to the procedureoutlined above:

[1133] a) N-(4-tert-Butyl-3-nitro-phenyl)-2-chloro-nicotinamide.

[1134] b)2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1135] c)2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1136] d)2-Chloro-N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1137] e)2-Chloro-N-[3-(l-methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[1138] f)2-Chloro-N-[3-(1-isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[1139] g) (S)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.

[1140] h)2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide.

[1141] i)2-Chloro-N-[3-(2-piperidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[1142] j) (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[1143] k) (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.

[1144] l) (R)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1145] m) (S)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1146] n) (R)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.

[1147] o) (R) Acetic acid2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethylester.

[1148] p)2-Chloro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1149] q)2-Chloro-N-[2-(4-methoxy-benzyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-nicotinamide.M+H 450.2. Calc'd 449.

[1150] r)2-Chloro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.M+H 330.1, Calc'd 329.

[1151] s)2-Chloro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1152] t)2-{3-[(2-Chloro-pyridine-3-carbonyl)-amino]-phenyl}-2-methyl-propionicacid methyl ester. M+H 405

[1153] u)N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-chloro-nicotinamide.M+Na 524. Calc'd 501.1.

[1154] v)N-[3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-6-yl]-2-chloro-nicotinamide.

[1155] w)N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-chloro-nicotinamide.

[1156] x)2-Chloro-N-[3,3-dimethyl-2,3-dihydro-benzofuran-6-yl]-2-chloro-nicotinamide.

[1157] y)2-Chloro-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1158] z)2-Chloro-N-[3-(1-methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1159] aa)2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1160] ab)N-[4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenyl]-2-chloro-nicotinamide.

[1161] ac) (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1162] ad) (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

PreparationVI—1-Boc-2-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine

[1163]1-Boc-2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidinewas prepared from1-Boc-2-(3-amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation VII—2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[1164] 1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine(2.35 g) was dissolved in CH₂Cl₂ (60 ml) and TFA (20 ml) was added.After stirring for 1 h at RT, the mixture was concentrated in vacuo toyield 2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oilthat solidified upon standing. The material was used as is withoutfurther purification.

[1165] The following compounds were prepared similarly to the procedureoutlined above:

[1166] a)(4-Aminomethyl-pyrimidin-2-yl)-(3-morpholin-4-yl-propyl)-amine.

[1167] b)(4-Aminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.

PreparationVIII—1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

[1168] 2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol)was dissolved in CH₃CN (20 ml) and formaldehyde (2.4 ml, 37% aqueous)was added. NaBH₃CN (607 mg) was added, an exotherm was observed. The pHis monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min,the mixture was concentrated in vacuo and the residue is dissolved inEtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washingswere combined, adjusted to ˜pH 10 with solid Na₂CO₃ and extracted withEtOAc (2×). The EtOAc fractions were combined, dried with Na₂SO₄, andpurified with flash chromatography (SiO₂, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH) toafford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

[1169] The following compounds were prepared similarly to the procedureoutlined above:

[1170] a) 2-(l-Methylpiperidin-4-yl)-ethanol.

[1171] b)2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-1-methylpyrrolidine.

Preparation IX—4-tert-butyl-3-nitro-phenylamine

[1172] A mixture of 1,3-dinitro-4-tert-butylbenzene (10.0 g) in H₂O (56ml) was heated to reflux. A mixture of Na₂S (21.42 g) and sulfur (2.85g) in H₂O (34 ml) was added over 1 h via an addition funnel. Thereaction maintained at reflux for 1.5 h then cooled to RT and extractedwith EtOAc. The organic extracts were combined and washed with H₂O,brine, dried over MgSO₄ and concentrated in vacuo to afford4-tert-butyl-3-nitro-phenylamine which was used as is without furtherpurification.

Preparation X—N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide

[1173] 3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) wasdissolved in AcOH (140 ml) and Ac₂O (5.9 ml, Aldrich) was added. Thereaction was stirred at RT overnight. The mixture was added slowly toH₂O (˜700 ml) forming a white precipitate. The solid was isolated byfiltration, washed with H₂O and dried under vacuum to yieldN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide.

PreparationXI—N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

[1174] Allylpiperidine (1.96 g, Lancaster) was degassed under vacuum,dissolved in 0.5 M 9-BBN in THF (31.2 ml, Aldrich), and heated to refluxfor 1 h, then cooled to RT. PD(dppf)Cl₂/CH₂Cl₂ was added to a degassedmixture of N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide, K₂CO₃ (9.8 g)DMF (32.1 ml and H₂O (3 ml). The allyl piperidine solution was addedheated to 60° C. for 3 h. After cooling to RT and reheating at 60° C.for 6 h, the mixture was cooled to RT and poured into H₂O. The mixturewas extracted with EtOAc (2×), and the EtOAc portion was washed with 2 NHCl (2×) and brine. The aqueous phases were combined and the pH wasadjusted to ˜11 with NaOH (15%) forming a cloudy suspension. The cloudysuspension was extracted with EtOAc (2×) and the EtOAc portion was driedwith Na₂SO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH) toaffordN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide as abrown oil that solidified under vacuum.

[1175] The following compounds were prepared similarly to the procedureoutlined above:

[1176] a) N-(3-Morpholin-4-ylpropyl-5-trifluoromethyl-phenyl)-acetamidefrom 4-allyl-morpholine.

[1177] b)N-(3-(1-methylpiperdin-4-ylmethyl-5-trifluoromethyl-phenyl)-acetamidefrom 1-Methyl-4-methylene-piperidine.

PreparationXII—3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine

[1178]N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide (1.33g) was dissolved in EtOH (40 ml) and 12 N HCl (40 ml) was added. Afterstirring overnight at 70 ° C. and RT, the mixture was concentrated invacuo, affording3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine as a brownoil.

[1179] The following compounds were prepared similarly to the procedureoutlined above:

[1180] a) 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole. M+H 193.1; Calc'd192.2.

[1181] b)3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenylamine.

[1182] c) 3-Morpholin-4-ylmethyl-5-trifluoromethyl-phenylamine.

PreparationXIII—3,3-Dimethyl-6-nitro-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indole

[1183]3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indolewas dissolved in HCl/EtOAc and stirred for 2 h. The mixture wasconcentrated in vacuo and partitioned between 1,2-dichloroethane and iNNaOH. The organic layer was removed, washed with brine, dried (Na₂SO₄)and filtered. The material was used without further purification.

PreparationXIV—N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

[1184]N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide wasprepared from allyl morpholine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation ofN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

Preparation XV—3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine

[1185] 3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine wasprepared fromN-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamidesimilar to that described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XVI—1-methyl-4-methylene-piperidine

[1186] Ph₃PCH₃I (50 g, Aldrich) was suspended in Et₂O (20 ml) andbutyllithium (77.3 ml, 1.6 M in hexanes, Aldrich) was added dropwise.The reaction was stirred for 2 h at RT then 1-methylpiperidone (12.3 ml,Aldrich) was added slowly. The mixture was stirred at RT overnight. Thesolid was removed by filtration, the volume was reduced to ˜400 ml andadditional solid was removed by filtration. The Et₂O was washed with H₂O(2×) and 2N HCl (4×). The pH of the acid washings was adjusted to ˜11with 6 N NaOH, then they were extracted with CH₂Cl₂ (4×). The CH₂Cl₂washings were dried over Na₂SO₄ and concentrated cold in vacuo toprovide 1-methyl-4-methylene-piperidine which was used as is.

PreparationXVII—N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide

[1187] N-[3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamidewas prepared from 1-methyl-4-methylene-piperidine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation ofN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

PreparationXVIII—3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine

[1188] 3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine wasprepared fromN-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamidesimilar to the procedure described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XIX—2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile

[1189] 4-Hydroxy-1-methylpiperidine (25.4 g) was dissolved in THF (50ml) in a 100 mL r.b. flask. NaH/mineral oil mixture (9.58 g) was slowlyadded to the flask and stirred for 20 min. 2-Chloro-4-cyanopyridine wasadded to the mixture and stirred at RT until completion. Diluted mixturewith EtOAc and added H₂O to quench mixture, then transferred contents toa sep. funnel. The organic phase was collected while the aqueous phasewas washed two times with EtOAc. The combined organics were dried overNa₂SO₄, filtered, then concentrated in vacuo. Then redissolved mixturein CH₂Cl₂, 10% HCl (300 ml) was added and the mixture was transferred tosep. funnel. The org. was extracted, while EtOAc along with 300 mL 5NNaOH was added to the sep. funnel. The organic phases were collected,dried over Na₂SO₄, filtered and concentrated in vacuo affording2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile as a brown solid.ESI (M+H)=218.

[1190] The following compounds were prepared similarly to the procedureoutlined above:

[1191] a) 2-(1-methylpiperidin-4-ylmethoxy)-4-pyridylcarbonitrile. M+H232.1. Calc'd 231.1.

[1192] b) 2-(1-Benzhydryl-azetidin-3-yloxy)-4-pyridylcarbonitrile. M+H342.2. Calc'd 341.2.

[1193] c) 2-(1-methylpiperidin-4-ylethoxy)-4-pyridylcarbonitrile.

[1194] d) 2-(1-pyrrolidinylethoxy)-4-pyridylcarbonitrile.

[1195] e) 2-(1-methylpyrrolin-2-ylethoxy)-4-pyridylcarbonitrile.

[1196] f) 2-[2-(1-Boc-azetidin-3-yl)-ethoxy]-4-pyridylcarbonitrile.

Preparation XX—[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylaminebis hydrochloride

[1197] [2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine wasdiluted with Et₂O (50 ml) and 1M HCl/Et₂O (47 ml) was added. The vesselwas swirled until precipitate formed.

Preparation XXI—2-(2-morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile

[1198] 2-(2-Morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile was preparedfrom 2-chloro-4-cyanopyridine and 2-morpholin-4-yl-ethanol by aprocedure similar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. The hydrochloridesalt was prepared similar to that described for[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine bishydrochloride.

Preparation XXII—2-morpholin-4-yl-propanol

[1199] LAH powder (1.6 g) was added to a flask while under N₂atmosphere, immediately followed by THF (50 ml). The mixture was chilledto 0° C., methyl 2-morpholin-4-yl-propionate (5 g) was added dropwise tothe reaction mixture and stirred at 0° C. After 1 h, the mixture wasworked up by adding H₂O (44 mL), 2N NaOH (44 mL), then H₂O (44 mL, 3×).After 30 min of stirring, the mixture was filtered through Celite® andthe organic portion was concentrated in vacuo providing2-morpholin-4-yl-propanol as a colorless oil.

[1200] The following compounds were prepared similarly to the procedureoutlined above:

[1201] a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

Preparation XXIII—2-(2-morpholin-4-yl-propoxy)-4-pyridylcarbonitrile

[1202] 2-(2-Morpholin-4-yl-propoxy)-4-pyridylcarbonitrile was preparedfrom 2-chloro-4-cyanopyridine and 2-morpholin-4-yl-propanol by aprocedure similar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile.

PreparationXXIV—2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile

[1203] 2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile wasprepared from 2-chloro-4-cyanopyridine and1-methyl-pyrrolidin-2-ylmethanol by a procedure similar to thatdescribed in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. ESI MS: (M+H)=218.

Preparation XXV—2-(3-morpholin-4-yl-propylamino)-4-pyridylcarbonitrile

[1204] To a flask charged with 2-chloro-4-cyanopyridine (2.0 g), wasadded the aminopropyl morpholine (2.11 ml). The mixture was heated to79° C. for 5 h and stirred. After 5 h the reaction was incomplete. Themixture was then heated at 60° C. overnight. The crude compound waspurified on silica gel (1-5% MeOH/CH₂Cl₂ gradient). ESI MS: (M+H)=247,(M−H)=245.

Preparation XXVI—5-Nitro-2-pentafluoroethylphenol

[1205] Combined 2-methoxy-4-nitro-1-pentafluoroethylbenzene (9.35 g) andpyridine hydrochloride in a round bottom flask and heated at 210° C. for1 h then cooled to RT. The mixture was diluted with EtOAc and 2N HCl(>500 ml) until all residue dissolved. The organic layer was removed,washed with 2N HCl (2×) and concentrated in vacuo. The residue wasdissolved in hexanes and Et₂O, washed with 2N HCl, then brine. Driedorganic layer over Na₂SO₄, filtered, concentrated in vacuo and driedunder high vacuum to provide 5-nitro-2-pentafluoromethylphenol.

Preparation XXVII—2-tert-Butyl-5-nitro-aniline

[1206] To H₂SO₄ (98%, 389 mL) in a 500 mL 3-neck flask was added2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. andKNO3 in 3.89 g aliquots was added every 6 min for a total of 10aliquots. Tried to maintain temperature at −5° C. to −10° C. After finaladdition of KNO₃, stirred the reaction for five min then it was pouredonto ice (50 g). The black mix was diluted with H₂O and extracted withEtOAc. The aqueous layer was basified with solid NaOH slowly thenextracted with EtOAc (2×). The combined organic layers were washed with6N NaOH and then with a mix of 6N NaOH and brine, dried over Na₂SO₄,filtered and concentrated in vacuo to obtain crude2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidifiedwhen standing at RT. The crude material was triturated with about 130 mLhexanes. After decanting the hexanes, the material was dried to obtain adark-red black solid.

Preparation XXVIII—2-tert-Butyl-5-nitrophenol

[1207] In a 250 ml round bottom flask, 20 mL concentrated H₂SO4 wasadded to 2-tert-butyl-5-nitro-aniline (7.15 g) by adding 5 mL aliquotsof acid and sonicating with occasional heating until all of the startinganiline went into solution. H₂O (84 ml) was added with stirring, thenthe reaction was cooled to 0° C. forming a yellow-orange suspension. Asolution of NaNO₂ (2.792 g) in H₂O (11.2 mL) was added dropwise to thesuspension and stirred for 5 min. Excess NaNO₂ was neutralized withurea, then the cloudy solution was transferred to 500 ml 3-necked roundbottom flask then added 17 mL of 1:2 H₂SO₄:H₂O solution, and heated atreflux. Two additional 5 mL aliquots of 1:2 H₂SO₄:H₂O solution, a 7 mLaliquot of 1:2 H₂SO₄:H₂O solution and another 10 mL of 1:2 H₂SO₄: H₂Owere added while heating at reflux. The mixture was cooled to RT forminga black layer floating on top of the aqueous layer. The black layer wasdiluted with EtOAc (300 mL) and separated. The organic layer was washedwith H₂O then brine, dried over Na₂SO₄ and concentrated in vacuo. Crudeoil was purified on silica gel column with 8% EtOAc/Hexanes. Upon dryingunder vacuum, the 2-tert-butyl-5-nitrophenol was isolated as a brownsolid.

Preparation XXIX—1-methylpiperidine-4-carboxylic acid ethyl ester

[1208] Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved inMeOH (1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42ml) were added and stirred for 2 h. The mixture was cooled to 0° C.,NaCNBH₃ (70 g) was added, and the mix was stirred for 20 min at 0° C.,then overnight at RT. The mixture was cooled to 0° C. then quenched with6N NaOH. The mixture was concentrated in vacuo to an aqueous layer,which was extracted with EtOAc (4×), brine-washed, dried over Na₂SO₄,and concentrated in vacuo to provide 1-methylpiperidine-4-carboxylicacid ethyl ester.

[1209] The following compounds were prepared similarly to the procedureoutlined above:

[1210] a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

PreparationXXX—N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide

[1211]N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamidewas prepared from4-tert-butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XXXI—1-[2-(2-tert-Butyl-5-nitro-phenoxy)-ethyl]-piperidine

[1212] To 2-tert-butyl-5-nitrophenol (1.01 g) and K₂CO₃ (1.72 g) wasadded acetone (35 ml) and H₂O (10.5 mL), then1-(2-chloroethyl)piperidine HCl (1.909 g) and TBAI (153 mg). The mixturewas stirred at ref lux overnight. Additional K₂CO₃ (850 mg) and1-(2-chloroethyl)-piperidine HCl (950 mg) were added and the mixture washeated at reflux for 6 h. The mixture was concentrated in vacuo to anaqueous layer which was acidified with 2N HCl and extracted with EtOAc.The aqueous layer was basified with 6N NaOH and washed with CH₂Cl₂ (3×).The combined organic layers were washed with brine/1N NaOH and driedover Na₂SO₄. Washed the EtOAc layer with 2N NaOH/brine and dried overNa₂SO₄. The crude material was purified by silica gel columnchromatography with 15% EtOAc/Hexanes to yield1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine as a light tansolid. (M+1)=307.3.

Preparation XXXII—1-Boc-Piperidine-4-carboxylic acid ethyl ester

[1213] To a stirred solution of piperidine-4-carboxylic acid ethyl ester(23.5 g) in EtOAc (118 ml) at 0° C. was added dropwise Boc₂O in EtOAc(60 ml). The reaction was warmed to RT and stirred overnight. Washedreaction with H₂O, 0.1N HCl, H₂O, NaHCO₃ and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The liquidwas dried under vacuum to provide 1-Boc-piperidine-4-carboxylic acidethyl ester.

[1214] The following compounds were prepared similarly to the procedureoutlined above:

[1215] a) N-Boc-(2-chloropyrimidin-4-yl)-methylamine.

[1216] b) 1-(2-tert-Butyl-4-nitrophenyl)-4-Boc-piperazine.

[1217] c) 1-Boc-azetidine-3-carboxylic acid

[1218] d) 1-Boc-4-Hydroxymethyl-piperidine using TEA.

Preparation XXXIII—1-Boc-4-hydroxymethyl-piperidine

[1219] 1-Boc-4-Hydroxymethyl-piperidine was prepared from1-Boc-piperidine-4-carboxylic acid ethyl ester by a procedure similar tothat described in the preparation of 2-morpholin-4-yl-propanol.

Preparation XXXIV—1-Boc-4-Methylsulfonyloxymethyl-piperidine

[1220] Dissolved 1-Boc-4-hydroxymethyl-piperidine in anhydrous CH₂Cl₂(50 ml) and TEA (4.5 ml) and cooled to 0° C. Mesyl chloride (840 μl) wasadded and the mixture was stirred for 15 min then at RT for 45 min. Themixture was washed with brine/1N HCl and then brine, dried over Na₂SO₄,concentrated in vacuo and dried under high vacuum to provide1-Boc-4-methylsulfonyloxymethyl-piperidine as a yellow orange thick oil.

[1221] The following compounds were prepared similarly to the procedureoutlined above:

[1222] a) 1-Boc-3-methylsulfonyloxymethyl-azetidine.

PreparationXXXIV—1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[1223] To a slurry of 60% NaH suspension in DMF (30 mL) at RT added asolution of 5-nitro-2-pentafluoroethyl-phenol (3.6 g) in 5 mL DMF. Thedark red mixture was stirred at RT for 10 min then added a solution of1-Boc-4-methylsulfonyloxymethyl-piperidine (3.1 g) in 5 mL DMF. Thereaction was stirred at 60° C. and 95° C. After 1 h, added 2.94 g K₂CO₃and stirred overnight at 105° C. After cooling to RT, the reaction wasdiluted with hexanes and 1N NaOH. Separated layers, and washed organiclayer with 1N NaOH and with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification with silica gel columnchromatography with 8% EtOAc/Hexanes yielded1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine as a lightyellow thick oil.

PreparationXXXVI—4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[1224] 4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine wasprepared from1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine by aprocedure similar to that described in the preparation of2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

PreparationXXXVII—1-methyl-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

[1225] 4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine (316.5mg) was dissolved in 2.7 mL acetonitrile, then added 37%formaldehyde/H₂O (360 ul) and then NaBH₃CN (90 mg). Upon addition ofNaCNBH₃ the reaction exothermed slightly. The reaction was stirred at RTand pH was maintained at ˜7 by addition of drops of glacial acetic acid.After about 1 h, the mixture was concentrated in vacuo, treated with 8mL 2N KOH and extracted two times with 10 mL Et₂O. The organic layerswere washed with 0.5N KOH and then the combined organic layers wereextracted two times with 1N HCl. The aqueous layer was basified withsolid KOH and extracted two times with Et₂O. This organic layer was thenwashed with brine/1N NaOH, dried over Na₂SO₄, filtered, concentrated invacuo and dried under high vacuum to give pure compound.

PreparationXXXVIII—1-Isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine

[1226] Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine(646 mg) in 1,2-dichloroethane (6.4 ml), then added acetone (136 ul),NaBH(OAc)₃ (541 mg) and finally acetic acid (105 ul). Stirred the cloudyyellow solution under N₂ at RT overnight. Added another 130 uL acetoneand stirred at RT over weekend. Quenched the reaction with 30 mL NNaOH/H₂O and stirred 10 min. Extracted with Et₂O and the organic layerwas brine-washed, dried over Na₂SO₄, filtered and concentrated in vacuo.Dried under high vacuum for several h to obtain1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as ayellow orange solid.

[1227] The following compounds were prepared similarly to the procedureoutlined above:

[1228] a)3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indolewas prepared using 1-methyl-piperidin-4-one. M+H 290; Calc'd 289.4.

[1229] b)3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indoleusing 1-Boc-4-formyl-piperidine.

PreparationXXXIX—3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole

[1230] 3,3-Dimethyl-1-piperidin-4-ylmethyl-6-nitro-2,3-dihydro-1H-indolewas treated with an excess of formaldehyde and NaBH(OAc)₃ and stirredovernight at RT. The reaction was quenched with MeOH and concentrated invacuo. The residue was partitioned between EtOAc and 1N NaOH. Theorganic layer was removed, washed with brine, dried (Na₂SO₄), filteredand concentrated to provide the compound.

Preparation XL—(S) 2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane

[1231] Combined 5-nitro-2-pentafluoromethylphenol (2.69 g), DMF (25 ml)K₂CO₃ (3.03 g) and (S) toluene-4-sulfonic acid oxiranyl-methyl ester(2.27 g) and stirred the mixture at 90° C. After about 4 hours, the mixwas cooled, diluted with EtOAc, washed with H₂O, 1N NaOH (2×), 1N HCland then with brine. Dried over Na₂SO₄, filtered and concentrated invacuo. Purified the crude on silica gel column with 5% EtOAc/hexane anddrying under high vacuum provided the(S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

[1232] The following compounds were prepared similarly to the procedureoutlined above:

[1233] a) (R)-2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

Preparation XLI—(S)2-Chloro-N-[3-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[1234] (S)2-Chloro-N-[4-(2-oxiranylmethoxy-)-3-pentafluoroethyl-phenyl]-nicotinamide(1.11 g) in a sealed tube and added pyrrolidine (285 μl). Stirred aftersealing tube at 60° C. After 12 h, the mix was concentrated in vacuo andpurified on a silica gel column (5:95:0.5 MeOH:CH₂Cl₂:NH₄OH—8:92:1,MeOH:CH₂Cl₂:NH₄OH). Concentrated in vacuo and dried under high vacuum toobtain pure compound.

[1235] The following compounds were prepared similarly to the procedureoutlined above:

[1236] a) (R)1-(5-Nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol.

Preparation XLII—5-nitro-2-trifluoromethylanisole

[1237] Cooled 140 mL pyridine in a large sealable vessel to −40° C.Bubbled in trifluoromethyl iodide from a gas cylinder which had beenkept in freezer overnight. After adding ICF₃ for 20 min, added2-iodo-5-nitroanisole (24.63 g) and copper powder (67.25 g). Sealedvessel and stirred vigorously for 22 h at 140° C. After cooling to −50°C., carefully unsealed reaction vessel and poured onto ice and Et₂O.Repeatedly washed with Et₂O and H₂O. Allowed the ice-Et₂O mixture towarm to RT. Separated layers, washed organic layer with 1N HCl (3×),then brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Eluted material through silica gel plug (4.5:1 Hex:CH₂Cl₂) to provide5-nitro-2-trifluoromethylanisole.

PreparationXLIII—1-[2-(5-nitro-2-trifluoromethylphenoxy)ethyl]pyrrolidine

[1238] 1-[2-(5-Nitro-2-trifluoromethylphenoxy)ethyl]-pyrrolidine wasprepared from 5-nitro-2-trifluoromethyl-phenol and1-(2-chloroethyl)pyrrolidine by a procedure similar to that describedfor 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLIV—1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine

[1239] 1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine wasprepared from 5-nitro-2-pentafluoroethylphenol and1-(2-chloroethyl)piperidine by a procedure similar to that described inthe preparation of1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLV—3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine

[1240] 3-(2-Pyrrolidin-1-yl-methoxy)-4-trifluoromethyl-phenylamine wasprepared from 1-[2-(5-nitro-2-trifluoromethylphenoxy)methyl]-pyrrolidineby a procedure similar to that described in the preparation of1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine.

PreparationXLVI—2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

[1241]2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamidewas prepared from3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine and2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-(3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XLVII—(R) Acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester

[1242] Dissolved1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol(3.5 g) in CH₂Cl₂ (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetylchloride (781.3 μl) was added dropwise, forming a suspension. Themixture was warmed to RT and stirred for 1.5 h. Additional acetylchloride (200 μl) was added and the mix was stirred for another h. Themixture was diluted with CH₂Cl₂ and washed with sat. NaHCO₃. The organiclayer was removed, washed with brine and back extracted with CH₂Cl₂.Dried the combined organic layers over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified over silica gel column (5:94.5:0.5MeOH: CH₂Cl₂:NH₄OH) to provide acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester as a yellow brown oil.

[1243] The following compounds were prepared similarly to the procedureoutlined above:

[1244] a) (R) Acetic acid2-(5-amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-methyl-ethylester.

[1245] b)1-(2,2-Dimethyl-6-nitro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone.M-NO₂ 206.4; Calc'd 250.1.

Preparation XLVIII—(R)2-Chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

[1246] (R) Acetic acid2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethylester (408 mg) was dissolved in MeOH (15 ml) and NH₄OH (6 ml) was addedand the mixture was stirred at RT for 6 h. The reaction was concentratedin vacuo and dried under high vacuum. The residue was purified oversilica gel column (8:92:0.6 MeOH: CH₂Cl₂:NH₄OH). The purified fractionswere concentrated in vacuo and dried again to provide(R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamideas a white foam.

PreparationXLIX—2-Dimethylamino-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone

[1247] 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole (5 g) was dissolved inDMF (100 ml) and HOAt (3.89 g) dimethylamino-acetic acid (5.83 g) andEDC (3.89 g) were added. The reaction was stirred overnight. The mixturewas diluted with CH₂Cl₂ (1 L) and washed with sat'd NaHCO₃ (3×200 ml).The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂, EtOAc to 5%MeOH/EtOAc) to afford the title compound.

[1248] The following compounds were prepared similarly to the procedureoutlined above:

[1249] a)1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone.

PreparationL—1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1yl)-2-(N-Boc-amino)-ethanone

[1250]1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone(3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH₄Cl (299mg) and H₂O (5 ml) were added. The reaction was stirred at 80° C.overnight. The reaction was filtered through Celite® and evaporated offthe MeOH. The residue was partitioned between CH₂Cl₂ and sat'd NaHCO₃.The organic layer was removed, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (SiO₂, 25% EtOAc/hexane). The purified fractions wereconcentrated in vacuo to afford the compound as a white powder.

[1251] The following compounds were prepared similarly to the procedureoutlined above:

[1252] a)1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-dimethylamino-ethanone.

[1253] b)3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.

[1254] c)3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine. M+H324.2. Calc'd 323.

[1255] d)3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-ylamine.M+H 259.6; Calc'd 259.3.

[1256] e)3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-116-benzo[d]isothiazol-6-ylamine

[1257] f) 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-ylamine.

[1258] g)3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.

PreparationLI—2-Boc-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

[1259] 4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (150 mg) wasdissolved with CH₂Cl₂ (3 ml) DIEA (100 ul) DMAP (208 mg and Boc₂O (204mg) and the mixture was stirred for 6 h at RT. The reaction was dilutedwith CH₂Cl₂, washed with sat'd NaHCO₃ and dried over MgSO₄, filtered andconcentrated to provide the compound which was used without furtherpurification.

[1260] The following compounds were prepared similarly to the procedureoutlined above substituting Ac₂O:

[1261] a)1-(4,4-Dimethyl-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone. M+H249.3.

Preparation LII—2-Bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide

[1262] PMB-amine (5.35 ml) in CH₂Cl₂ (130 ml) was slowly added to2-bromo-5-nitro-benzoyl chloride (10.55 g) and NaHCO₃ (9.6 g) and themixture was stirred at RT for 1 h. The mixture was diluted with CH₂Cl₂(1 L), filtered, washed with dilute HCl, dried, filtered again,concentrated and dried under vacuum to provide the compound as a whitesolid. M+H 367. Calc'd 366.

PreparationLIII—2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide

[1263] To a suspension of NaH (1.22 g) in DMF (130 ml) was added2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 ml) at−78° C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57g) was added and the mixture was stirred for 2 h at 0° C. The reactionwas poured into ice water, extracted with EtOAc (2×400 ml), dried overMgSO₄, filtered and concentrated to a DMF solution which was usedwithout further purification.

Preparation LIV—of2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

[1264] 2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide(23.4 mmol) was dissolved in DMF (150 ml) and Et₄NCl (4.25 g), HCO₂Na(1.75 g) and NaOAc (4.99 g) were added. N₂ was bubbled through thesolution for 10 min, then Pd(OAc)₂ (490 mg) was added and the mixturewas stirred overnight at 70° C. The mixture was extracted with EtOAc,washed with sat'd NH₄Cl, dried over MgSO₄, filtered and concentrateduntil the compound precipitated as a white solid.

[1265] The following compounds were prepared similarly to the procedureoutlined above:

[1266] a) 3,3-Dimethyl-6-nitro-2,3-dihydro-benzofuran was prepared from1-bromo-2-(2-methyl-allyloxy)-4-nitro-benzene.

[1267] b) 3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene wasprepared from4-[1-(2-bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine.

Preparation LV—4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

[1268]2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one(2.0 g) was dissolved in CH₃CN (100 ml) and H₂O (50 ml) and cooled to 0°C. CAN (9.64 g) was added and the reaction was stirred at 0° C. for 30min, then warmed to RT and stirred for 6 h. The mixture was extractedwith CH₂Cl₂ (2×300 ml) washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The crude material was recrystallized inCH₂Cl₂/EtOAc (1:1) to give4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one as a white solid.

Preparation LVI—4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

[1269] 4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (230 mg)was dissolved in THF (10 ml) and BH₃Me₂S (400 ul) was added and thereaction was stirred overnight at RT. The reaction was quenched withMeOH (10 ml) and NaOH (200 mg) and heating at reflux for 20 min. Themixture was extracted with EtOAc, washed with sat'd NH₄Cl, extractedwith 10% HCl (20 ml). The acidic solution was treated with 5N NaOH (15ml), extracted with EtOAc (30 ml) dried, filtered and evaporated to givethe compound as a yellow solid. M+H 207.2, Calc'd 206.

[1270] The following compounds were prepared similarly to the procedureoutlined above:

[1271] a) 4-Boc-2,2-dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine.

Preparation LVII—2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene

[1272] 2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) wasdissolved in CCl₄ (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added.The reaction was heated to reflux and stirred for 24 h. The mix wasdiluted with CH₂Cl₂, washed with sat'd NaHCO₃, dried over MgSO₄ andconcentrated to give the compound as an oil which was used withoutfurther purification.

PreparationLVIII—1-Methyl-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

[1273] 2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.6 g) wasadded to N-methylpiperazine (5 ml) and stirred at RT for 3 h. Themixture was filtered and the filtrate was treated with 1-chlorobutane,extracted with 2N HCl (100 ml). The acidic solution was treated with 5NNaOH (6 ml) then extracted with EtOAc. The organic layer was removed,dried over MgSO₄ and concentrated to give the compound as an oil.

[1274] The following compounds were prepared similarly to the procedureoutlined above:

[1275] a) 4-(5-Nitro-2-pentafluoroethyl-benzyl)-morpholine.

Preparation LIX—1-Boc-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine.

[1276] 2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.5 g) wasdissolved in CH₂Cl₂ and added to N-Boc-piperazine (2.5 g) and NaHCO₃ (1g) and stirred at RT overnight. The mixture was diluted with CH₂Cl₂ (100ml), washed with sat'd NH₄Cl, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(hexane, CH₂Cl₂:hexane 2:8) to give the compound as an yellow solid.

PreparationLX—(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone

[1277] A mixture of 3-nitro-5-trifluoromethyl-benzoic acid (4.13 g),4-Boc-piperazine (2.97 g), EDC (3.88 g), HOBt (2.74 g), DIEA (3.33 ml)in CH₂Cl₂ (120 ml) was stirred at RT for 3 h. The mixture was dilutedwith CH₂Cl₂ (100 ml), washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The residue was purified by silica gelchromatography (hexane, CH₂Cl₂:hexane 1:2) to give the compound as awhite solid.

Preparation LXI—1-Boc-4-(3-nitro-5-trifluoromethyl-benzyl)-piperazine

[1278](4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone (403mg) was dissolved in THF (6 ml) and BH₃Me₂S (300 μl) was added and thereaction was stirred for 3 h at 60° C. and 2 h at RT. The reaction wasquenched with MeOH (5 ml) and NaOH (100 mg) and stirred at RT for 1 h.The mixture was concentrated and dissolved in CH₂Cl₂, washed with satedNH₄Cl/NaHCO₃, dried (MgSO₄), filtered and evaporated to give thecompound as an oil. M+H 390.3.

Preparation LXII—2-Ethyl-4-aminomethyl pyridine

[1279] To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250ml) was added Raney 2800 Nickel (5 g, Aldrich) in one portion. Themixture was stirred at RT for 2 days then at 60° C. for 16 h. Themixture was filtered, concentrated to provide the desired compound.

PreparationLXIII—N-Boc-[2-(4-morpholin-4-yl-butyl)-pyrimidin-4-ylmethyl]-amine

[1280] N-Boc-(2-chloropyrimidine)-methylamine (663 mg) and4-(aminopropyl)morpholine (786 mg) were dissolved in MeOH andconcentrated in vacuo. The residue was heated at 100° C. for 15 min,forming a solid which was dissolved in CH₂Cl₂/MeOH then concentratedagain and heated 15 min more. Concentrated in vacuo and dried under highvacuum. Triturated with a small amount of IpOH and allowed to settleover a weekend. Filtered, rinsing with a small amount of IpOH to providethe compound as a white solid.

[1281] The following compounds were prepared similarly to the procedureoutlined above:

[1282] a)(4-Bocaminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.M+H 336.5; Calc'd 335.45.

Preparation LXIV—2-fluoronicotinic acid

[1283] In a flame dried 3-necked round bottom flask equipped with adropping funnel and thermometer, under N₂, THF (250 ml) was added viacannula. LDA (2M in cyclohexane, 54 ml) was added via cannula as theflask was cooled to −78° C. At −78° C., 2-fluoropyridine (8.87 ml) wasadded dropwise over 10 min. The reaction was stirred for 3 h.Condensation was blown off (with N₂) a few cubes of solid CO₂ and theywere added to the mixture. The mixture was warmed to RT once thesolution turned yellow, and it was stirred overnight. The reaction wascooled to 0° C. and the pH was adjusted to ˜2.5 with 5N HCl. The mixturewas concentrated in vacuo and extracted with EtOAc. The EtOAc layer waswashed with brine, dried over MgSO₄, filtered and concentrated todryness. The resulting solid was slurried in EtOAc (100 ml), filtered,washed with cold EtOAc and dried at 50° C. for 1 h to afford2-fluoronictinic acid. M+H 142.1; Calc'd 141.0.

Preparation LXV—4-cyano-2-methoxypyridine

[1284] Under a stream of N₂ and with cooling, Na metal (2.7 g) was addedto MeOH (36 ml) with a considerable exotherm. After the Na is dissolved,a solution of 2-chloro-4-cyanopyridine (15 g) in dioxane:MeOH (1:1, 110ml) was added via dropping funnel over a 10 min period. The reaction washeated to reflux for 3.5 h then cooled at ˜10° C. overnight. Solid wasfiltered off and the solid was washed with MeOH. The filtrate wasconcentrated to ˜60 ml and H₂O (60 ml) was added to redissolve aprecipitate. Upon further concentration, a precipitate formed which waswashed with H₂O. Further concentration produced additional solids. Thesolids were combined and dried in vacuo overnight at 35° C. to provide4-cyano-2-methoxypyridine which was used as is.

Preparation LXVI—(2-methoxypyridin-4-yl)methylamine

[1285] 4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml)and conc. HCl (4.96 ml) was added. Pd/C (10%) was added and H₂ was addedand let stand overnight. The solids were filtered through Celite® andthe cake was washed with MeOH (˜250 ml). Concentration in vacuo producedan oil which was dissolved in MeOH (˜20 ml). Et₂O (200 ml) was added andstirred for 1 h. The resulting precipitate was filtered and washed withEt₂O to afford (2-methoxypyridin-4-yl)methylamine (hydrochloride salt)as an off-white solid.

Preparation LXVII—2-(4-Amino-phenyl)-2-methyl-propionic acid methylester

[1286] 2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g)was dissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) wereadded. The mixture was stirred for 1 h and filtered through Celite®. Thefiltrate was rinsed with EtOAc and the organics were evaporated to aresidue which was purified on silica gel chromatography(40%EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H194.

Preparation LXVIII—1-(2-tert-Butyl-phenyl)-4-methyl-piperazine

[1287] 2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylaminewere mixed together with K₂CO₃ (25 g), NaI (10 g) and diglyme (250 mL)and heated at 170° C. for 8 h. Cooled and filtered solid and evaporatedsolvent. Diluted with EtOAc, washed with NaHCO₃ solution, extractedtwice more with EtOAc, washed with brine, dried over Na₂SO₄ andevaporated to give the compound as a dark solid.

[1288] The following compounds were prepared similarly to the procedureoutlined above:

[1289] a) 1-Bromo-2-(2-methyl-allyloxy)-4-nitro-benzene was preparedfrom methallyl bromide.

Preparation LXIX3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

[1290]3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(8.8 g, 0.032 mol)was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mol)and 2NNa₂CO₃ aqueous solution (25mL) was bubbled through N₂ for 5 min.Pd(PPh₃)₄ (3.7 g, 3.2 mmol) was added and the reaction was heated to 80°C. for 16 h. The reaction was cooled to RT and diluted with Et₂O (100mL). The mixture was filtered through Celite® and the filtrate waswashed with NaHCO₃ aqueous solution (25 ml) followed by brine (25 mL).The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Thedesired product was isolated by passing through silica gel columnchromatography (EtOAc, then (2M NH₃) in MeOH/EtOAc) to provide a yellowoil.

Preparation LXX—3,3-Dimethyl-6-nitro-2,3-dihydro-benzo[d]isothiazole1,1-dioxide

[1291] 3,3-Dimethyl-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide wasadded to KNO₃ in H₂SO₄ cooled to 0° C. and stirred for 15 min. Thereaction was warmed to RT and stirred overnight. The mix was poured intoice and extracted with EtOAc (3×), washed with H₂O and brine, dried andevaporated to give the product which was used without furtherpurification.

[1292] The following compounds were prepared similarly to the procedureoutlined above:

[1293] a) 1,1,4,4-Tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene

PreparationLXXI—3-(1-Methyl-1,2,3,4-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

[1294]3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(1.2 g) was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (1.0 g), LiCl (500 mg,Aldrich), PPh₃ (300 mg, Aldrich) and 2M Na₂CO₃ aqueous solution (6 ml)and was bubbled with N₂ for 5 min. Pd(PPH₃)₄ (300 mg, Aldrich) was addedand the reaction was heated to 80° C. for 16 h. The reaction was cooledto RT and diluted with Et₂O (100 mL). The mixture was filtered throughCelite® and the filtrate was washed with NaHCO₃ aqueous solution (25 ml)followed by brine (25 mL). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The desired compound was isolated by silica gelcolumn chromatography (EtOAc 10% (2M NH₃) in MeOH/EtOAc) to provideyellow oil. M+H 257.2; Calc'd 256.1.

Preparation LXXII—Trifluoromethylsulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester

[1295] In a three-necked round bottom flask equipped with a thermometerand an additional funnel was placed anhydrous THF (200 mL) and 2M LDA(82.8 mL). The solution was cooled to−78° C. and a solution of1-methyl-piperidin-4-one (20 mL) in anhydrous THF (70 mL) was addeddrop-wise. The reaction was warmed to −10° C. over 30 min and cooleddown again to −78° C. Tf₂NPh (54.32 g) in 200 mL of anhydrous THF wasadded through the additional funnel over 30 min and anhydrous THF (30mL) was added to rinse the funnel. The reaction was warmed to RT and thereaction solution was concentrated in vacuo. The residue was dissolvedin Et₂O purified on neutral Al₂O₃ column chromatography (Et₂O aselutant). The product was obtained as orange oil. (20 g)

PreparationLXXIII—3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine

[1296] N₂ was bubbled through a solution of3-bromo-5-trifluoromethyl-phenylamine (2.38 g),5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl](2.24 g, FrontierScientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) in anhydrousdioxane (50 ml) for 2 min. PdCl₂ (dppf) (243 mg, Aldrich) was added andthe reaction was heated to 80° C. for 4 h. After cooling to RT, the mixwas diluted with 50 mL of Et₂O, filtered through Celite®, and thefiltrate was concentrated in vacuo. The residue was dissolved in Et₂O(100 mL), washed with sat. NaHCO₃ aqueous solution (50 mL) followed bybrine (50 mL). The organic phase was dried over Na₂SO₄ and concentratedin vacuo. The residue was dissolved in 3:2 Et₂O/Hex (100 mL), filteredthrough Celite® and the filtrate was concentrated in vacuo to afford adark brown semi-solid.

Preparation LXXIV—1-Boc-3-Hydroxymethyl-azetidine

[1297] A solution of 1-Boc-azetidine-3-carboxylic acid (1.6 g) and Et₃N(2 ml) in anhydrous THF (60 ml) was cooled to 0° C. Isopropylchloroformate (1.3 g) was added via a syringe slowly; forming a whiteprecipitate almost immediately. The reaction was stirred for 1 h at 0°C. and the precipitate was filtered out. The filtrate was cooled to 0°C. again and aqueous NaBH₄ solution (900 mg, 5 ml) was added via pipetteand stirred for 1 h. The reaction was quenched with NaHCO₃ solution (50mL) and the product was extracted with EtOAc (200 mL). The organic phasewas washed with brine (50 mL), dried over Na₂SO₄ and concentrated invacuo. The residue was dissolved in EtOAc and passed through a shortsilica gel pad. Concentrating the filtrate in vacuo provided thecompound as a light yellow oil.

PreparationLXXV—1-Boc-3-(3-nitro-5-trifluoromethyl-phenoxymethyl)-azetidine

[1298] A mixture of 1-Boc-3-methylsulfonyloxymethyl-azetidine (1.47 g),3-nitro-5-trifluoromethyl-phenol (1.15 g) and K₂CO₃ (1.15 g) in DMF(20ml) at 80° C. was stirred overnight. The reaction was cooled to RT anddiluted with 25 mL of sat. NaHCO₃ and 50 mL of EtOAc. The organic phasewas separated and washed with brine (25 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude compound was purified by columnchromatography (50% EtOAc/hex).

Preparation LXXVI—2,2-Dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine

[1299] 2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one was added toBH₃-THF complex (Aldrich) in THF with ice cooling. The mixture washeated to reflux for 2 h then carefully diluted with 12 mL of MeOH andheated to reflux for an additional 1 h. Concentrated HCl (12 mL) wasadded and heated to reflux for 1 h. The mixture was concentrated and theresulting solid was suspended in a dilute aqueous solution of NaOH (1 M)and extracted with EtOAc (100 mL×4). The organic layers were washed withH₂O and dried over MgSO₄. Evaporation of solvent gave a yellow solid.

Preparation LXXVII—2,2,4-Trimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

[1300] 2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixedwith MeI (850 mg, Aldrich), K₂CO₃ (1.38 g, Aldrich) and DMF (30 ml,Aldrich) at 40° C. for 48 h. The DMF was removed in vacuo and theresidue was diluted with EtOAc (80 ml). The organic phase was washedwith H₂O (50 ml), aqueous Na₂SO₃ (50 ml) and brine (50 ml). Theresulting solution was dried (MgSO₄) and concentrated to provide thecompound which was used as is.

PreparationLXXVIII—2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide

[1301] 2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47ml, Aldrich) and Et₃N (2.0 g, Aldrich) was slowly added via syringe. Themixture was stirred for 45 min then poured into ice. The aqueous phasewas extracted by EtOAc (50 mL×4). The organic layer was dried andconcentrated. The desired product was crystallized from EtOAc. (Chem.Pharm. Bull 1996, 44(1) 103-114).

Preparation LXXIX—2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

[1302] 2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide wasmixed with K₂CO₃ in 20 mL of DMF and stirred overnight at 50° C. Thereaction mixture was poured into ice water. The precipitate wascollected by filtration and washed with H₂O. The crude compound wasrecrystallized from EtOH.

PreparationLXXX—4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide

[1303] 1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium (8 g)was dissolved in glacial HOAc (10 ml) then diluted with H₂SO₄ (50 ml),then NBS (3.8 g) was added. After 1 h, additional NBS (1.2 g) was added,30 min later another 0.5 g of NBS, then 15 min later 200 mg more NBS.After 1 h, the mixture was neutralized with NH₄OH (conc.) with ice bathcooling. The neutralized mixture was then concentrated and used as is.

PreparationLXXXI—4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine

[1304]4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodidewas mixed with MeOH (400 ml) and CH₂Cl₂ (200 ml), then treated withNaBH₄ (2.5 g) in portions. After stirring at RT for 2 h, the mixture wasextracted with CH₂Cl₂ (300 mL×3). The CH₂Cl₂ layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo, to provide thedesired product.

PreparationLXXXII—1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium iodide

[1305] 4-(4-Nitro-benzyl)-pyridine (4.3 g) was mixed with MeI (4 ml,9.12 g)/NaOH (5N, 30 ml), Bu₄NI (150 mg) and CH₂Cl₂ (50 ml) and stirredat RT overnight. Additional MeI (2 mL) was added along with 50 mL ofNaOH (5N). 6 h later, more MeI (2 mL) was added. The mixture was stirredat RT over the weekend. The mixture was cooled on ice bath and the basewas neutralized by conc. HCl (aq) addition dropwise to pH 7. Thecompound was used as is.

PreparationLXXXIII—1-Methyl-4-(4-nitro-benzyl)-1,2,3,6-tetrahydro-pyridine

[1306] 4-(4-Nitrobenzyl)pyridine (64 g) and TBAI (6 g) were dissolved inCH₂Cl₂ (500 mL) and the solution was suspended with NaOH (aq. 5N, 450mL) in a 3L 3-necked round bottom flask. With vigorous stirring,iodomethane (213 g) was added and stirred vigorously at RT for 60 h (oruntil blue color disappears). The reaction was quenched withdimethylamine (100 mL) and MeOH (300 mL) and stirred for 2 h. NaBH₄ (19g) was added to the mixture in small portions. The reaction mixture wasstirred for 30 min at RT, then partitioned between CH₂Cl₂/H₂O (500mL/500 mL). The organic layer was collected and the aqueous layer waswashed with CH₂Cl₂ (300 mL×3). The combined organic layers was washedwith brine then concentrated in vacuo. The residue was purified on asilica wash-column (7% TEA in EtOAc). The desired fractions werecombined and concentrated under vacuum to give the desired compound as adark gray solid. (MS: M+1=261).

Preparation LXXXIV—1-Boc-4-formylpiperidine

[1307] 4A Molecular sieves were heated to 100° C. and a vacuum wasapplied. They were cooled to RT and purged with N2. CH₂Cl₂ (420 ml) andCH₃CN (40 ml), NMO (40 g) and 1-Boc-4-hydroxymethylpiperidine (50 g)were added and the mix was stirred for 5 min then cooled to 15° C. TPAP(4.1 g) is added and an exotherm was observed. The reaction wasmaintained at RT with external cooling. The reaction was stirred at RTfor 3 h, filtered, concentrated, diluted with 50% EtOAc/hexanes andpurified on a silica gel plug (50%EtOAc/hexanes). The eluant fractionswere concentrated to afford a yellow oil.

Preparation LXXXV 2-Chloro-4-cyanopyridine

[1308] 2-Chloro-4-cyanopyridine was prepared similar to the methoddescribed by Daves et al., J. Het. Chem., 1, 130-32 (1964).

Preparation LXXXVI 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol

[1309] A mix of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3.652 g), TEA(5.92 ml), 3-buten-1-ol (5.48 ml), Pd(OAc)₂ (32 mg), Pd(PPh₃)₄ (327 mg)and toluene (40 ml) was degassed with nitrogen and heated in a sealedvessel for 16 h at 120° C. The next day, the reaction mixture was cooledto RT, filtered, and concentrated in vacuo. The crude was eluted on asilica gel column with 15% to 22% EtOAc/hexanes gradient system to yielda yellow-brown oil.

Preparation LXXXVII 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal

[1310] 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol (1.024 g) wasdissolved in 10 ml of CH₂Cl₂ and added dropwise over 5 min to a −78° C.mix of oxalyl chloride (0.645 ml), DMSO (0.583 ml), and 10 ml CH₂Cl₂.The reaction was stirred at −78° C. for 1 h, then treated with asolution of TEA (1.52 ml) in 7 ml CH₂Cl₂ and stirred at −78° C. for anadditional 25 min, then warmed to −30° C. for 35 min. The reaction wastreated with 50 ml of saturated aqueous NH₄Cl, diluted with H₂O andextracted with EtOAc. The organic layer was brine-washed, dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a yellow oil whichwas used as is in Preparation LXXXVIII.

Preparation LXXXVIII1-[4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine

[1311] 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal (895 mg) was dissolvedin 40 ml THF, and to the solution was added pyrrolidine (0.317 ml). Tothe deep orange solution was added NaBH(OAc)₃ (1.151 g) and glacial AcOH(0.207 ml). The reaction was stirred at RT overnight, then treated withsaturated aqueous NaHCO₃ and diluted with Et₂O and some 1N NaOH. Thelayers were separated, and the organic layer was extracted with aqueous2N HCl. The acidic aqueous layer was basified to pH>12 with 6 N NaOH,extracted with Et₂O, brine-washed, dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide1-[4-(2-tert-butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine as aorange-brown oil.

Preparation LXXXVIV N-Boc-(2-chloropyrimidin-4-yl)-methylamine

[1312] To 2-chloropyrimidine-4-carbonitrile [2.5 g, prepared by theprocedure of Daves et. al. [J. Het. Chem. 1964, 1, 130-132)] in EtOH(250 ml) under N₂ was added Boc₂O (7.3 g). After the mixture was brieflyplaced under high vacuum and flushed with N₂, 10% Pd/C (219 mg) wasadded. H₂ was bubbled though the mixture (using balloon pressure with aneedle outlet) as it stirred 4.2 h at RT. After filtration throughCelite®, addition of 1.0 g additional Boc₂O, and concentration, theresidue was purified by silica gel chromatography (5:1→4:1hexanes/EtOAc) to obtain N-Boc-(2-chloropyrimidin-4-yl)-methylamine.

EXAMPLE 1

[1313]

Step A—Preparation of3-[(tert-butoxy)carbonylamino]thiophene-2-carboxylic acid

[1314] To a mixture of methyl 3-amino-2-thiophenecarboxylate (8 g, 51mmol) and BOC₂O (11 g, 50 mmol) in CH₂Cl₂ (400 ml) was added4-(dimethylamino)pyridine (1 g, 8.1 mmol).

[1315] The reaction was stirred at RT overnight and washed with 1N HCl(100 ml), followed by water and brine. The organic layer was dried overNa₂SO₄ and evaporated under reduced pressure and used for the next stepwithout further purification. To the residue (2 g, ˜7 mmol) in EtOH (50ml) was added IN NaOH (25 ml), the reaction was stirred at RT for 1 hand the solvent was evaporated under reduced pressure. Water (5 ml) wasadded and the solution was acidified with HOAc. The precipitate wasfiltered and used in the next step without further purification. MS(ES−): 242 (M−H)⁻.

Step B—Preparation of{3-[(tert-butoxy)carbonylamino](2-thienyl)}-N-(4-chlorophenyl)carboxamide

[1316] To a mixture of the thienyl carboxylic acid from Step A (300 mg,1.23 mmol) and 4-chloroaniline (160 mg, 1.25 mmol) and DIEA (300 μl, 1.6mmol) was added EDC (300 mg, 1.6 mmol) and HOBt (170 mg, 1.25 mmol) inCH₂Cl₂, the reaction was stirred at RT overnight. The solution waswashed with 1N HCl and saturated NaHCO₃, followed by H₂O and brine. Theorganic layer was dried over Na₂SO₄ and evaporated under reducedpressure and purified with preparative TLC to give the amide. MS (ES+):353 (M+H)⁺; (ES−): 351 (M−H)⁻.

Step C—Preparation ofN-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

[1317] The amide from Step B was mixed with 25% TFA/CH₂Cl₂ and stirredat RT for 1 h (monitored by HPLC). The solvent was evaporated underreduced pressure and the residue was mixed with 4-pyridinecarboxaldehyde (260 mg, 2.5 mmol) and NaCNBH₃ (160 mg, 2.5 mmol) in MeOH(40 ml). The reaction was stirred at RT overnight and evaporated underreduced pressure. The final product was purified by prep-HPLC as TFAsalt. MS (ES+): 344 (M+H)⁺; (ES−) 342 (M−H). Calc'd. forC₁₇H₁₄ClN₃OS—343.84.

EXAMPLE 2

[1318]

[1319] The title compound was analogously synthesized by methoddescribed in Example 1. The final product was purified by preparativeHPLC as TFA salt. MS (ES+): 310 (M+H)⁺; (ES−): 308 (M−H)⁻. Calc'd. forC₁₇H₁₅N₃OS—309.4.

EXAMPLE 3

[1320]

Step A—Preparation of (2-amino(3-pyridyl))-N-(4-chlorophenyl)carboxamide

[1321] To a mixture of 2-aminonicotinic acid (5.3 g, 38 mmol) and4-chloroaniline (4.9 g, 38 mmol) and DIEA (9 ml, 48 mmol) at 0° C. inCH₂Cl₂ was added EDC (9.5 g, 48 mmol) and HOBt (5.1 g, 38 mmol), thereaction was warmed to RT and stirred overnight. The solvent wasevaporated under reduced pressure and quenched with 2N NaOH solution (60ml) and stirred for 20 min. The precipitate was filtered to give thetitled compound. MS (ES+): 248 (M+H)+; (ES−): 246 (M−H).

Step B—Preparation ofN-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1322] To a mixture of the pyridyl carboxamide (400 mg, 1.6 mmol) fromStep A and 4-pyridinecarboxaldehyde (200 μl, 2 mmol) and HOAc (200 μl)in CH₂Cl₂ was added NaBH(OAc)₃ (600 mg, 2.8 mmol), the reaction wasstirred at RT overnight. The reaction mixture was washed with H₂O andbrine and dried over Na₂SO₄. The solution was evaporated and purified byprep-TLC to give the title compound. MS (ES+): 339 (M+H)⁺; (ES−) 337(M−H)⁻. Calc'd for C₁₈H₁₅ClN₄O—338.796.

EXAMPLE 4

[1323]

[1324] The title compound was analogously synthesized by the methoddescribed in Example 3. MS (ES+): 373 (M+H)⁺; (ES−): 370.9 (M−H)⁻.Calc'd for C₁₈H₁₄Cl₂N₄O—373.24.

EXAMPLE 5

[1325]

[1326] The title compound was analogously synthesized by the methoddescribed in Example 3. MS (ES+): 339 (M+H)⁺; (ES=): 337 (M−H)⁻. Calc'd.for C₁₈H₁₅ClN₄O—338.1.

EXAMPLE 6

[1327]

[1328] The title compound was analogously synthesized by methoddescribed in Example 3. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻. Calc'd.for C₁₈H₁₅ClN₄O—338.8

EXAMPLE 7

[1329]

[1330] The title compound was analogously synthesized by the methoddescribed in Example 3. MS (ES+): 389 (M+H)⁺; (ES−): 387 (M−H)⁻. Calc'd.for C₂₂H₁₇ClN₄O—388.86.

EXAMPLE 8

[1331]

[1332] The title compound was analogously synthesized by the methoddescribed in Example 3. MS (ES+): 423 (M+H)⁺; (ES−): 421 (M−H)⁻. Calc'd.for C₂₂H₁₆Cl₂N₄O—423.30.

EXAMPLE 9

[1333]

Step A—Preparation of6-methyl-2-[(4-pyridylmethyl)amino]pyridine-3-carboxylic acid

[1334] The mixture of 2-chloro-6-methyl-nicotinic acid (1.0 eq.) and4-aminomethyl-pyridine (2.0 eq.) was stirred in a sealed tube at 130° C.overnight. The resulted mixture was cooled to RT, diluted with CH₂Cl₂,filtered to collected the brown solid. The brown solid wasrecrystallized in ethanol to give the substituted amine as light brownsolid. MS (ES+): 244 (M+H)⁺.

Step B—Preparation ofN-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

[1335] To the mixture of the substituted amine from Step A (1.0 eq.)and4-chloroaniline (2.0 eq) in CH₂Cl₂ was addedbis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.1 eq.) and TEA (1.1eq.). The mixture was stirred overnight, diluted with CH₂Cl₂, washedwith saturated NH₄Cl solution, dried over Na₂SO₄, filtered andconcentrated, purified by flash chromatography (4% MeOH/CH₂Cl₂) to givethe title compound as an white solid. MS (ES+): 353 (M+H); (ES−): 351(M−H). Calc'd. for C₁₉H₁₇ClN₄O—352.82.

EXAMPLE 10

[1336]

[1337] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 387 (M+H); (ES−): 385 (M−H) Calc'd.for C₁₉H₁₆Cl₂N₄O—387.27.

EXAMPLE 11

[1338]

[1339] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 351 (M+H); (ES−): 349 (M−H). Calc'd.for C₂₀H₁₉FN₄O—350.39.

EXAMPLE 12

[1340]

[1341] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 354 (M+H); (ES−): 352 (M−H). Calc'd.for C₁₈H₁₆ClN₅O—353.81.

EXAMPLE 13

[1342]

[1343] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 409 (M+H). Calc'd. forC₁₈H₁₉Cl₃N₄O—407.7.

EXAMPLE 14

[1344]

[1345] The title compound was analogously synthesized by methoddescribed in Example 9. MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd.for C₁₈H₁₄Cl₂N₄O—373.24.

EXAMPLE 15

[1346]

[1347] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 357 (M+H); (ES−): 355 (M−H). Calc'd.for C₁₈H₁₉FN₄OCl—356.5.

EXAMPLE 16

[1348]

[1349] The title compound was analogously synthesized by the methoddescribed in Example 9. MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd.for C₁₈H₁₄Cl₂N₄O—373.24.

EXAMPLE 17

[1350]

[1351] A mixture of (2-amino(4-pyridyl))-N-(4-chlorophenyl)carboxamide(350 mg, 1.4 mmol) (similar procedure to Example 3, Step A) and4-pyridine carboxaldehyde (200 μl, 2 mmol) and 4-toluenesulfonic acidmonohydrate (50 mg) in EtOH (50 ml) was heated to reflux overnight. Thesolvent was evaporated and the residue was purified by prep-TLC. MS(ES+): 337 (M+H)⁺; (ES−): 335 (M−H)⁻. Calc'd. for C₁₈H₁₃ClN₄O—336.8.

EXAMPLE 18

[1352]

[1353] The compound from Example 17 was mixed with NaBH₄ (100 mg) inEtOH (20 ml) and heated to reflux for 5 min. The solvent was evaporatedunder reduced pressure and the residue was purified by prep-TLC to givethe titled compound. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻. Calc'd.for C₁₈H₁₅ClN₄O—338.8.

EXAMPLE 19

[1354]

[1355] The title compound was analogously synthesized by the method inExamples 17-18. MS (ES−): 337 (M−H)⁻. Calc'd. for C₁₉H₁₇FN₄O—336.37.

EXAMPLE 20

[1356]

[1357] The title compound was analogously synthesized by the methoddescribed in Examples 17-18. MS (ES+): 389 (M+H)⁺; (ES−) 387 (M−H)⁻.Calc'd. for C₂₂H₁₇ClN₄O—388.86.

EXAMPLE 21

[1358]

[1359] The title compound was analogously synthesized by the methoddescribed in Examples 17-18. MS (ES+): 389 (M+H)⁺; (ES−): 387 (M−H)⁻.Calc'd. for C₂₂H₁₇ClN₄O—388.86.

EXAMPLE 22

[1360]

Step A—Preparation of 5-bromo-2-hydroxynicotinic acid

[1361] A solution of sodium hypobromide was made by adding Br₂ (1.01 ml,39.5 mmol, 1.1 eq) slowly over a period of 5 min to NaOH (5N, 40 ml)that was previously cooled to 0° C. in an ice bath. The solution wasstirred for 10 min before adding 2-hydroxynicotinic acid (5.0 g, 35.9mmol) and placed in a 50° C. oil bath and stirred. Concurrently, asecond pot of sodium hypobromide solution was made by slowly adding Br₂(1.01 ml, 39.5 mmol, 1.1 eq) to a NaOH solution (5N, 40 ml) in an icebath. The second pot of sodium hypobromide was added to the solution of2-hydroxynicotinic acid after 24 h of heating then was stirred for anadditional 24 h. The solution was cooled to RT, placed in an ice bathand acidified with concentrated HCl while stirring. The precipitatewhich formed was filtered, washed and dried to afford the desiredcompound as an off-white solid.

Step B—Preparation of 5-bromo-2-chloronicotinic acid

[1362] A solution of 5-bromo-2-hydroxynicotinic acid, from Step A (8.3g, 38.1 mmol) and SOCl₂ (40 ml) in a 150 ml round bottom flask wasplaced in an 80° C. oil bath and stirred while adding 10 ml of DMF. Thesolution was heated at reflux for 4 h at 80° C. before cooling to RT.Excess SOCl₂ was stripped off under reduced pressure forming ayellow-brown residue. The yellow-brown residue was placed in an ice bathand cooled to 0° C. Residual SOCl₂ was neutralized and the chlorocompound was precipitated by the dropwise addition of water. Precipitatewas filtered, washed and dried to afford the desired chloro compound asa light yellow solid.

Step C—Preparation of 5-bromo-2-chloro-N-(4-chlorophenyl)nicotinamide

[1363] To a mixture of 4-chloroanaline (594 mg, 4.7 mmol, 1. eq.), EDC(1.62 g, 8.5 mmol, 2 eq.), HOBT (572 mg, 4.2 mmol, 1 eq.), and DIEA (1.1ml, 6.3 mmol, 1.5 eq.) in CH₂Cl₂ (50 ml) was added5-bromo-2-chloronicotinic acid from Step B (1.0 g, 4.2 mmol). Thereaction was stirred at RT overnight. The solution was quenched withwater and the organic layer was purified by chromatography (50% EtOAc inhexane) to afford a light-yellow compound. MS (ES+): 347.0, 349.0(M+H)⁺; (ES−): 345.0, 347.0 (M−H)⁻.

Step D—Preparation of5-(3-thiophene)-2-chloro-N-(4-chlorophenyl)nicotinamide

[1364] 3-Thiophene boronic acid (204 mg, 1.6 mmol, 1.1 eq), Pd(OAc)₂ (33mg, 0.2 mmol, 0.2 eq.), and K₂CO₃ (505 mg, 4.3 mmol, 3 eq.) were addedto a solution of 5-bromo-2-chloro-N-(4-chlorophenyl)nicotinamide fromStep C (500 mg, 1.4 mmol) in DMF (20 ml). The reaction was placed in a50° C. oil bath and stirred overnight. The reaction was filtered andpurified by medium pressure chromatography (30% EtOAc in hexane) toafford the desired thienyl compound as an off white solid.

Step E—Preparation ofN-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide

[1365] 4-(Aminoethyl)pyridine (10 ml) was added to a 25 ml round-bottomflask containing 5-(3-thiophene)-2-chloro-N-(4-chlorophenyl)nicotinamidefrom Step D (200 mg, 0.6 mmol). The solution was placed in an 80° C. oilbath and stirred overnight. The reaction was cooled to RT, and after anaqueous work-up, was purified by medium-pressure chromatography (80%EtOAc in hexane) to afford the title compound as a light yellow solid..MS: (ES+) 435.1 (M+H); (ES−) 432.8 (M−H). Calc'd. forC₂₃H₁₉ClN₄OS—434.95.

EXAMPLE 23

[1366]

[1367] The title compound was prepared analogously to Example 22. MS:(ES+) 445.1 (M+H). Calc'd. for C₂₅H₂₁ClN₄O—444.92.

EXAMPLE 24

[1368]

[1369] The title compound was prepared analogously to Example 22, StepsA, B, C and E. MS: (ES+) 419 (M+H) (ES−) 417 (M−H). Calc'd. forC₁₈H₁₄BrClN₄O—417.69.

EXAMPLE 25

[1370]

Step A: Preparation of(2-chloro-3-pyridyl)-N-(4-isopropylphenyl)carboxamide

[1371] To a mixture of 2-chloronicotinic acid (6.3 g) and4-isopropylaniline (5.26 ml) and DIEA (10 ml) in CH₂Cl₂ (200 ml) wasadded EDC (10 g) and HOBt (5.4 g). The reaction was stirred at RTovernight and washed with 2 N NaOH (100 ml), H₂O (250 ml) and brine (100ml). The organic layer was dried over Na₂SO₄ and evaporated to give(2-chloro-3-pyridyl)-N-(4-isopropylphenyl)-carboxamide.

Step B: Preparation ofN-[4-(isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

[1372] A mixture of(2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5 g, from StepA) and 4-aminomethylpyridine (0.71 ml) was heated at 130° C. neat for 3h. The reaction was cooled and diluted with CH₂Cl₂ and washed with H₂Otwice followed by brine. The organic layer was dried with Na₂SO₄ andevaporated under reduced pressure. The residue was purified by columnchromatography with EtOAc and further mixed with MeOH and 1 N HCl/Et₂O(2 ml). The solution was evaporated to furnish the titled compound. MS(ES+): 347 (M+H)⁺; (ES−): 345 (M−H). Calc'd. for C₂₁H₂₂N₄O—346.18.

[1373] The following compounds (Examples 26-81) were synthesized by themethod described in Example 25 unless specifically described. Detailedintermediate preparations are included. TABLE 1

# Y R¹ R² M + H calc'd 26 —NH—CH₂—

H 347 346.2 27 NH—CH₂—

H 356 355.1 28 NH—CH₂—

H 471 470.1 29 NH—CH₂—

H 352 351.4 30 NH—CH₂—

H 365 364.2 31 NH—CH₂—

H 368 367.5 32 NH—CH₂—

H 369 368.5 33 NH—CH₂—

H 377 376.2 34 NH—CH₂—

H 366.8 366.8 35 NH—CH₂—

5-Br 447.0 445.7 36 NH—CH₂—

H 425.0 424.5 37 NH—CH₂—

H 363.2 362.4 38 NH—CH₂—

H 393.2 392.4 39 NH—CH₂—

H 393.2 392.4 40 NH—CH₂—

H 350.8 350.4 41 NH—CH₂—

H 389.2 388.5 42 NH—CH₂—

H 351.0 350.4 43 NH—CH₂—

H 367.1 366.8 44 NH—CH₂—

H 401.3 400.4 45 NH—CH₂—

H 377.2 376.5 46 NH—CH₂—

H 361.4 360.4 47 NH—CH₂—

H 377.1 376.4 48 NH—CH₂—

H 347.1 346.4 49 NH—CH₂—

H 349.1 348.4 50 NH—CH₂—

H 393.2 392.4 51 NH—CH₂—

H 411.2 411.3 52 NH—CH₂—

H 403.1 401.3 53 NH—CH₂—

H 415.2 414.4 54 NH—CH₂—

H 393.2 392.4 55 NH—CH₂—

H 403.2 401.3 56 NH—CH₂—

H 351.0 350.4 57 NH—CH₂—

H 369.1 366.8 58 NH—CH₂—

H 412.3 411.5 59 NH—CH₂—

H 338.8 338.4 60 NH—CH₂—

H 334.1 333.4 61 NH—CH₂—

H 333.6 333.4 62 NH—CH₂—

H 333.6 333.4 63 NH—CH₂—

H 361.1 360.4 64 NH—CH₂—

H 379.0 378.4 65 NH—CH₂—

H 399 398.9 66 NH—CH₂—

H 522.3 521

EXAMPLE 67

[1374]

[1375]{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(methylethyl)phenyl]carboxamide(50 mg, 0.125 mmol, from Example 66) dissolved in EtOH (10 mL) with TEA(0.5 mL) and suspended with Pd/C (10%, 5 mg). The mixture was stirred atRT under a H₂ balloon for 45 min. The mixture was filtered through alayer of Celite® and the filtrate was concentrated in vacuo. The residuewas partitioned between CH₂Cl₂ and aq. NaHCO₃ (sat.). The organicsolution was dried over Na₂SO₄ and concentrated in vacuo to give thetitle compound. MS: 365 (M+1). Calc'd. for C₂₁H₂₁FN₄O—364.42.

EXAMPLE 68

[1376]

Step A Preparation of 2-bromo-1-tert-butyl-4-nitrobenzene

[1377] NBS (125.0 g, 697.5 mmol) was slowly added to a solution ofTFA:H₂SO₄ (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0mmol) at RT. The solution was stirred for 24 h then poured over 5 kg ofice. The resulting suspension was filtered and washed with a 1:1MeOH:H₂O solution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1,260.1 (M+H)⁺. Calc'd for C₁₀H₁₂BrNO₂: 257.01.

Step B Preparation of 4-(2-tert-butyl-5-nitrophenyl)pyridine

[1378] To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3mmol) and toluene (70 mL) in a 150 mL round bottom flask,4-pyridylboronic acid (4.5 g, 36.6 mmol), Pd(PPh₃)₄ (3.8 g, 3.3 mmol)and K₂CO₃ (13.8 g, 99.9 mmol) were added. The solution was stirred for24 h at 80° C. before cooling to RT. The solution was filtered through apad of Celite® and purified by silica flash chromatography (30%EtOAc/Hexanes). This afforded the desired compound as a yellow solid. MS(ES+): 257.2 (M+H)⁺; (ES−): 255.2 (M−H)⁻. Calc'd for C₁₅H₁₆N₂O₂: 256.12.

Step C Preparation of 4-(2-tert-butyl-5-nitrophenyl)-1-methylpyridinium

[1379] 4-(2-tert-Butyl-5-nitrophenyl)pyridine (2.0 g, 7.8 mmol, Step B)was added to a round-bottom flask and dissolved in EtOH (10 mL). MeI (30mL) was added and the flask was placed in an 80° C. sand bath and heatedto reflux. After 6 h the solution was cooled to RT and the excess MeIand EtOH was concentrated in vacuo resulting in the desired compound asa light brown solid. MS (ES+): 271.2 (M+H)⁺; (ES−): 269.2 (M−H)⁻. Calc'dfor C₁₆H₁₉N₂O₂ ⁺: 271.14.

Step D Preparation of4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[1380] 4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8mmol, Step C) was added to a 100 mL round-bottom flask and dissolved ina 10% H₂O/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol) andNH₄Cl (460 mg, 8.6 mmol) were added. The flask was placed in a 100° C.sand bath and heated to reflux. After 2 h the solution was cooled to RTand filtered through a pad of Celite®. The resulting solution wasconcentrated in vacuo to a yellow solid and re-dissolved in MeOH (20 mL,anhydrous). The solution was cooled to 0° C. by placing it in an icebath and slowly adding NaBH₄ (450 mg, 11.7 mmol). After addition of theNaBH₄, the solution was cooled to RT and stirred for 30 min. The solventwas concentrated in vacuo and the solid was re-dissolved in CH₂Cl₂ andfiltered. The solution was again concentrated in vacuo to afford anamorphous clear yellow solid. MS (ES+): 245.2 (M+H)⁺. Calc'd forC₁₆H₂₄N₂: 244.19.

Step E Preparation of2-[(pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamide

[1381] The titled compound was prepared from4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline (Step D)by the method described in Example 25. MS: (ES+) 456.3 (M+H); (ES−)454.4 (M−H). Calc'd for C₂₈H₃₃N₅O—455.59.

EXAMPLE 69

[1382]

[1383] A mixture ofN-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and2-morpholin-4-ylethylamine (300 μL) was stirred at 80° C. for 20 h. Thereaction mixture was purified on silica gel chromatography to yieldN-(3,4-dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide.MS (ES+): 501 (M+H)⁺; (ES−): 499 (M−H)⁻. Calc'd forC₂₄H₂₆Cl₂N₆O₂—500.15.

EXAMPLE 70

[1384]

Step A Preparation of 4-[(4-nitrophenyl)methyl]morpholine

[1385] A mixture of nitrobenzyl bromide (648 mg, 3.0 mmol) andmorpholine (522 mg, 6.0 mmol) in CH₂Cl₂ was stirred for 5 h at RT.Filtration to remove the white solid, and the filtrate was concentratedto give 4-[(4-nitrophenyl)-methyl]morpholine as a solid, which was usedin next step without further purification.

Step B Preparation of 4-(morpholin-4-ylmethyl)phenylamine

[1386] A mixture of 4-[(4-nitrophenyl)methyl]morpholine (220 mg, 1.0mmol, Step A), iron powder (279 mg, 5.0 mmol) and NH₄Cl (39 mg, 0.7mmol) in EtOH (3 mL) and H₂O (3 mL) was stirred for 4 h at 80° C.Filtration and concentration gave the crude4-(morpholin-4-ylmethyl)-phenylamine, which was used in next stepwithout further purification.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1387] The titled compound was prepared from4-(morpholin-4-ylmethyl)phenylamine (Step B) by the method described inExample 25. MS (ES+): 404 (M+H); (ES−): 402 (M−H). Calc'd. forC₂₂H₂₄N₄O₂—403.20.

EXAMPLE 71

[1388]

Step A Preparation of(tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide

[1389] A mixture of 2-(4-nitrophenyl)ethylamine (1.01 g, 5.0 mmol), anddi-tert-butyl dicarbonate (1.09 g, 5.0 mmol) in CH₂Cl₂ (20 mL) and 1NNaOH (20 mL) was stirred for 20 h at RT. The mixture was extracted withCH₂Cl₂, washed with brine, and dried with MgSO₄. Filtration andconcentration yielded(tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide, which was used innext step without further purification.

Step B Preparation of N-[2-(4-aminophenyl)ethyl](tert-butoxy)carboxamide

[1390] A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide(570 mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH₄Cl(82 mg, 1.5 mmol) in EtOH (6 mL) and H₂O (6 ml) was stirred for 4 h at80° C. Filtration and concentration gave the crude compound, which wasused in next step without further purification.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1391] The titled compound was prepared fromN-[2-(4-aminophenyl)ethyl](tert-butoxy)carboxamide (Step B) by themethod described in Example 25. MS (ES+): 448 (M+H); (ES−): 446 (M−H).Calc'd. for C₂₅H₂₉N₅O₃—447.23.

EXAMPLE 72

[1392]

[1393] To the solution ofN-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(96 mg, 0.22 mmol, Example 71) in CH₂Cl₂ (3 mL) was added TFA (3 mL).The mixture was stirred for 3 h at RT. The reaction mixture wasconcentrated and dried in vacuo to yieldN-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide.MS (ES+): 348 (M+H); (ES−): 346 (M−H). Calc'd. for C₂₀H₂₁N₅O—347.17.

[1394] The following compounds (Example a-m) were synthesized by themethod described above, unless specifically described.

[1395] a)N-[3-(azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1396] b)2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.M+H 512.3; Calc'd 511.7.

[1397] c)N-[3-(piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 485.3.

[1398] d)N-[3-(piperazine-1-methyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 521.4.

[1399] c)N-[3-(piperazine-1-methyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 471.2; Calc'd 470.

[1400] d)N-[1-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]nicotinamide.M+H 461.1.

[1401] e)N-[1-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]nicotinamide.M+H 431.4.

[1402] f) (S)N-[3-(pyrrolidin-2-yl-methoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 522.6; Calc'd 521.5.

[1403] g) (R)N-[3-(pyrrolidin-2-yl-methoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 472.6; Calc'd 471.5.

[1404] h) (R)N-[3-(pyrrolidin-2-yl-methoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 522.3; Calc'd 521.5.

[1405] i) (S)N-[3-(pyrrolidin-2-yl-methoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-yl-methyl)-amino]-nicotinamide.M+H 472; Calc'd 471.5.

[1406] j) (S)N-[3-(4-piperdinyloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 472; Calcld 471.5.

[1407] k)2-[(2-Methoxy-pyridin-4-yl-methyl)-amino]-N-[3-(piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1408] l)N-{4-tert-Butyl-3-[2-(piperidin-4-yl)-methoxy]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 474.

[1409] m)N-[4-tert-Butyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 460.

[1410] n)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1411] o)N-(3,3-Dimethyl-1-pyrrolidin-2-ylmethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

EXAMPLE 73

[1412]

[1413] MS (ES+): 406 (M+H); (ES−): 405 (M−H). Calc'd. forC₂₂H₂₃N₅O₃—405.18.

EXAMPLE 74

[1414]

[1415] A mixture ofN-[4-(tert-butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide(100 mg, 0.25 mmol, Example 73), iron powder (69 mg, 1.25 nmol) andNH₄Cl (10 mg, 0.17 mmol) in EtOH (0.5 mL) and H₂O (0.5 ml) was stirredfor 4 h at 80° C. The reaction mixture was filtered, concentrated, andpurified through column chromatography to give the product. MS (ES+):376M+H);(ES−):374(M−H). Calc'd. for C₂₂H₂₅N₅O—375.21.

EXAMPLE 75

[1416]

[1417] MS (ES+): 347 (M+H); (ES−): 345 (M−H). Calc'd. forC₂₁H₂₂N₄O—346.18.

EXAMPLE 76

[1418]

[1419] MS (ES+): 418 (M+H); (ES−): 416 (M−H). Calc'd. forC₁₈H₁₆N₅O₃S—417.07.

EXAMPLE 77

[1420]

Step A Preparation of 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene

[1421] A mixture of 3-nitrobezenesulfonyl chloride (664 mg, 3.0 mmol)and methylpiperazine (600 mg, 6.0 mmol) in EtOH was stirred for 2 h atRT. The reaction was concentrated and triturated in Et₂O to yield ayellowish solid, 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene, andwas used in next step without further purification.

Step B Preparation of 3-[(4-methylpiperazinyl)sulfonyl]phenylamine

[1422] 3-[(4-Methylpiperazinyl)sulfonyl]phenylamine was analogouslysynthesized from 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene (StepA) by the method described in Example 74, which was used in next stepwithout further purification. MS (ES+): 256 (M+H). Calc'd. forC₁₁H₁₇N₃O₂S—255.10.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1423] The titled compound was prepared from3-[(4-methylpiperazinyl)sulfonyl]phenylamine (Step B) by the methoddescribed in Example 25. MS (ES+): 467 (M+H): (ES−): 465 (M−H). Calc'd.for C₂₃H₂₆N6O₃S—466.18.

EXAMPLE 78

[1424]

Step A Preparation of 4-(1,1,2,2,2-pentafluoroethyl)phenylamine

[1425] 1-Nitro-4-(1,1,2,2,2-pentafluoroethyl)benzene was synthesized bythe method described in the reference [John N. Freskos, SyntheticCommunications, 18(9), 965-972 (1988)]. It was reduced with Fe similarto that described in Example 74. It was used in next step withoutfurther purification.

Step B Preparation ofN-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1426] The titled compound was prepared from4-(1,1,2,2,2-pentafluoroethyl)phenylamine (Step A) by the methoddescribed in Example 25. MS (ES+): 423 (M+H); (ES−): 421 (M−H). Calc'd.for C₂₀H₁₅FN₄O—422.12.

EXAMPLE 79

[1427]

Step A Preparation of 4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine

[1428] The title intermediate was analogously synthesized by the methoddescribed of W. A. Gregory, et al. [J. Med. Chem., 1990, 33, 2569-2578].1-nitro-4-(1,1,2,2,3,3,4,4-monofluorobutyl) benzene was reduced with Fedescribed in Example 68, Step D, and used in next step without furtherpurification.

Step B Preparation ofN-[4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1429] The titled compound was prepared from4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine (Step A) by the methoddescribed in Example 25. MS (ES+): 523 (M+H); (ES−): 521 (M−H). Calc'd.for C₂₂H₁₅F₉N₄O—522.37.

EXAMPLE 80

[1430]

Step A Preparation of 2-(1,2,4-triazolyl)ethylamine

[1431] A mixture of (tert-butoxy)-N-(2-chloroethyl)-carboxamide (900 mg,5 mmol), 1,2,4-triazole (690 mg, 10 mmol) and Na₂CO₃ (1.06 g, 10 mmol)in DMF (3 mL) was stirred overnight at 100° C. The mixture was filteredand concentrated to give an oil. The oil was treated with TFA (10 mL)and stirred for 3 h. The reaction was concentrated to give the titledintermediate, which was used in next step without further purification.

Step B Preparation ofN-[4-(methylethyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamide

[1432] The titled compound was prepared from2-(1,2,4-triazolyl)ethylamine (Step A) by the method described inExample 25. MS (ES+): 351 (M+H); (ES−): 349 (M−H). Calc'd. forC₁₉H₂₂N₆O—350.19.

EXAMPLE 81

[1433]

Step A Preparation of 2-(2-pyridylamino)ethylamine

[1434] Ethylenediamine (6 g, 0.1 mol) and 2-fluoropyridine (10 g, 0.1mol) were heated neat at 120° C. overnight. The reaction was cooled andthe residue was used in next step without further purification.

Step B Preparation of (2-{[2-(2-pyridylamino)ethyl]amino}-(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[1435] The titled compound was prepared from2-(2-pyridylamino)ethylamine (Step A) by the method described in Example25. MS (ES+): 402 (M+H); (ES−): 400 (M−H). Calc'd. forC₂₀H₁₈F₃N₅O—401.15.

EXAMPLE 82

[1436]

Step A: Preparation of(2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide

[1437] 2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) inCH₂Cl₂ (100 ml) was added dropwise (via an addition funnel) to a stirredsolution of 3-(trifluoromethyl)-aniline (15.00 g, 0.093 mol) and DIEA(24.39 ml, 0.14 mol) in CH₂Cl₂ (500 ml) at 0° C. The mixture graduallywas warmed to RT. The reaction continued for 18 h before washing severaltimes with saturated NaHCO₃ aqueous solution and brine, respectively.The organic layer was dried over Na₂SO₄ and evaporated. The resultingoil was purified over silica gel with EtOAc/hexane (2:1) as eluant toleave the amide as a white solid (26.08 g). MS: (ES+) 301 (M+1)⁺; (ES−):299 (M−1)⁻. Calc'd for C₁₃H₈ClF₃N₂O: 300.03.

Step B: Preparation ofN-[3-trifluoromethylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

[1438] The amide (10.0 g 0.033 mol, Step A) and 4-aminomethylpyridine(10.81 g, 0.10 mol) were combined and heated at 120° C. for 4 h. Aftercooling to RT, the residue was dissolved in EtOAc and washed severaltimes with saturated NaHCO₃ aqueous solution and brine, respectively.The organic layer was dried over Na₂SO₄ and evaporated. The crude yellowoil was purified over silica gel with EtOAc as eluant to leave an amberoil (10.9 g). The free base was dissolved in MeOH (20 ml) and treatedwith a HCl ethereal solution (1.0 eq.). The solvent was evaporated toleave the salt as a white solid. The HCl salt was dried in vacuo at 30°C. for 24 h. MS: (ES+) 373 (M+1)⁺; (ES−): 371 (M−1)⁻. Calc'd. forC₁₉H₁₅F₃N₄O—372.12.

[1439] The following compounds (Examples 83-138) were analogouslysynthesized by the method described in Example 82 unless specificallydescribed. Detailed intermediate preparations are included. TABLE 2

# Y R¹ R² M + H calc'd 83 —NH—CH₂—

H 356 355.14 84 —NH—CH₂—

H 431 430.12 85 —NH—CH₂—

H 359 358.1 86 —NH—CH₂—

H 355 354.15 87 —NH—CH₂—

H 359 358.18 88 —NH—CH₂—

H 349 348.128 89 —NH—CH₂—

H 355 354.15 90 —NH—CH₂—

H 395 394.18 91 —NH—CH₂—

H 339 338.12 92 —NH—CH₂—

H 339 338.12 93 —NH—CH₂—

H 345 344.16 94 —NH—CH₂—

H 361 360.20 95 —NH—CH₂—

H 361 360.20 96 —NH—CH₂—

H 319 318.5 97 —NH—CH₂—

H 389 388.11 98 —NH—CH₂—

H 333 332.16 99 —NH—CH₂—

H 361 360.2 100 —NH—CH₂—

H 431 430 101 —NH—CH₂—

H 349 348.16 102 —NH—CH₂—

H 333 332.16 103 —NH—CH₂—

H 457 456.18 104 —NH—CH₂—

H 381 380.16 105 —NH—CH₂—

H 395 394.18 106 —NH—CH₂—

H 334 333.16 107 —NH—CH₂—

H 348 347.17 108 —NH—CH₂—

H 362 361.19 109 —NH—CH₂—

H 321 320.13 110 —NH—CH₂—

H 348 347.17 111 —NH—CH₂—

H 441 440.11 112 —NH—CH₂—

H 407 406.08 113 —NH—CH₂—

H 353 352.11 114 —NH—CH₂—

H 383 382.11 115 —NH—CH₂—

H 388 387.43 116 —NH—CH₂—

H 346 345.00 117 —NH—CH₂—

H 344 343.38 118 —NH—CH₂—

H 344 343.38 119 —NH—CH₂—

H 344 343.38 120 —NH—CH₂—

H 351 350.43 121 —NH—CH₂—

H 371 370.43

EXAMPLE 122

[1440]

[1441] MS: 411 (M+1); 409 (M−1). Calc'd. for C₂₅H₂₂N₄O₂—410.17.

EXAMPLE 123

[1442]

[1443] MS: (ES+) 452 (M+1)⁺; (ES−): 450 (M−1). Calc'd. forC₂₇H₂₁N₃O₂S—451.14.

EXAMPLE 124

[1444]

Step A—Preparation of{2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine

[1445] To a mixture of 2-nitro-4-tert-butylphenol (2 g) andN,N-dimethylethanolamine (1.3 g) and PPh₃ (4 g) in THF (50 ml) was addedDEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted withEtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer wasbasified with NaHCO₃, extracted with EtOAc twice and washed with H₂O andbrine. The organic layer was dried over Na₂SO₄ and evaporated to give{2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine, was used in nextstep without further purification.

Step B—Preparation of{2-[4-(tert-butyl)-2-aminophenoxy]-ethyl}dimethylamine

[1446] {2-[4-(tert-Butyl)-2-nitrophenoxy]-ethyl}dimethylamine (Step A)was hydrogenated under H₂ atmosphere to give{2-[4-(tert-butyl)-2-aminophenoxy]-ethyldimethylamine, and used in nextstep without further purification.

Step C—Preparation ofN-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1447] The titled compound was prepared from{2-[4-(tert-butyl)-2-aminophenoxy]-ethyldimethylamine (Step B) by themethod described in Example 82. MS (ES+): 448 (M+H); (ES−): 446 (M−H).Calc'd. for C₂₆H₃₃N₅O₂—447.26.

EXAMPLE 125

[1448]

Step A—Preparation of 1-[2-(tert-butylphenyl]-4-methylpiperazine

[1449] A mixture of 2-tert-butylaniline (5.4 g) andN-methylbis(2-chloroethyl)amine hydrochloride (7 g) and K₂CO₃ (5 g) inNaI (2 g) in diglyme (150 ml) was heated at 170° C. for 8 h. Thereaction was filtered and the filtrate was evaporated under high vacuum.The residue was mixed with EtOAc (200 ml) and H₂O (200 ml) and extractedwith EtOAc twice. The combined organic layer was washed with brine,dried over Na₂SO₄ and evaporated to give crude1-[2-(tert-butylphenyl]-4-methyl-piperazine, which was used in next stepwithout further purification.

Step B—Preparation of1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine

[1450] The crude 1-[2-(tert-butylphenyl]-4-methylpiperazine (260 mg,Step A) was stirred with H₂SO₄ (3 ml) at 0° C. and HNO₃ (1.2 ml) wasslowly added to the reaction. The reaction was warmed to RT, stirred for30 min. and poured on ice and basified with K₂CO₃ slowly. The solutionwas extracted with EtOAc three times, washed with H₂O, followed bybrine, dried over Na₂SO₄, and evaporated under reduced pressure. Theresidue was purified by column chromatography to give1-[2-(tert-butyl)-5-nitrophenyl]-4-methylpiperazine (260 mg), which washydrogenated under H₂ atmosphere to give1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine.

Step C—Preparation ofN-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl](2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1451] The titled compound was prepared from1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine (Step B) by themethod described in Example 82. MS (ES+): 459 (M+H); (ES−): 457 (M−H).Calc'd. for C₂₇H₃₄N₆O—458.28.

EXAMPLE 126

[1452]

Step A—Preparation of 3-(4-methylpiperazinyl)phenylamine

[1453] The intermediate was analogously synthesized from 3-nitroanilineby the method described in Example 130.

Step B—Preparation ofN-[3-(4-methylpiperazinyl)phenyl](2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1454] The titled compound was prepared from3-(4-methylpiperazinyl)phenylamine (Step A) by the method described inExample 82. MS (ES+): 403 (M+H); (ES−): 401 (M−H). Calc'd. forC₂₃H₂₆N₆O—402.22.

EXAMPLE 127

[1455]

Step A—Preparation of 4-methyl-1-(4-nitrophenyl)piperazine

[1456] 1-Fluoro-4-nitrobenzene (3.0 g, 0.021 mol) and 1-methylpiperazine(6.98 ml, 0.63 mol) were combined and heated neat at 90° C. for 48 h.Upon cooling to RT, the resulting brown oil solidified. The crudematerial was purified by re-crystallization from EtOAc/Hexane mixturesto leave the title compound as an orange solid (3.59 g). MS:

[1457] (ES+) 222 (M+1)⁺; (ES−): 220 (M−1)⁻. Calc'd for C₁₁H₁₅N₃O₂:221.12.

Step B—Preparation of 4-methyl-1-(4-aminophenyl)piperazine

[1458] 4-Methyl-1-(4-nitrophenyl)piperazine (2.0 g, 9 mmol, Step A) and10% Pd/C (200 mg) were added to EtOH/MeOH (1:1) (50 ml) at RT. Thereaction stirred under a H₂ atmosphere (via balloon) overnight. Themixture was filtered through a plug of Celiteo and the filtrate wasconcentrated under reduced pressure to leave the desired material as alight yellow oil. The material was used in subsequent reaction withoutpurification. MS: (ES+) 192 (M+1)⁺; (ES−): 190 (M−1)⁻. Calc'd forC₁₁H₁₇N₃: 191.14.

Step C Preparation ofN-[4-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide

[1459] The titled compound was prepared from4-methyl-1-(4-aminophenyl)piperazine (Step B) by the method described inExample 82. MS (ES+): 403 (M+H); (ES−): 401 (M−H). Calc'd. forC₂₃H₂₆N₆O—402.22.

EXAMPLE 128

[1460]

Step A—Preparation of 1-(1-methyl(4-piperidyl))-6-nitroindoline

[1461] 6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane,N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 gNaBH(OAc)₃ and 1 mL of glacial AcOH. The mixture was stirred at RTovernight. Saturated NaHCO₃ solution (200 mL) was added to the reactionmixture and stirred for 1 h. The resulting mixture was separated byseparation funnel, the organic layer was extracted once with saturatedNaHCO₃ solution and once with brine. The resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 2:1 EtOAc:MeOHto afford an orange oil. MS: 262 (M+1). Calc'd. for C₁₄H₁₉N₃O₂—261.32.

Step B—Preparation of 1-(1-methyl-4-piperidyl)indoline-6-ylamine

[1462] 1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g, Step A) wasdissolved in 100 mL MeOH, and the mixture was bubbled with N₂ for 10min. 10% Pd/C (200 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo to afford a light yellow oil. MS: 232 (M+1). Calc'd. forC₁₄H₂₁N₃—231.34.

Step C—Preparation ofN-[1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1463] The titled compound was prepared from1-(1-methyl-4-piperidyl)indoline-6-ylamine (Step B) by the methoddescribed in Example 82. MS: 443 (M+1). Calc'd. for C₂₆H₃₀N₆O—442.56.

EXAMPLE 129

[1464]

[1465] MS: 457 (M+1). Calc'd. for C₂₇H₃₂N₆O—456.58.

EXAMPLE 130

[1466]

Step A—Preparation of 1-(6-nitroindolinyl)-2-piperidylethan-1-one

[1467] 6-Nitroindoline (2.5 g) was dissolved in 200 mL of CH₂Cl₂,followed by DIEA (2.5 g). The mixture was cooled down to 0° C. in icebath. Chloroacetyl chloride (1.7 g) in 20 mL CH₂Cl₂ was added dropwiseto the mixture over 10 min and the mixture was stirred at RT overnight.The mixture was extracted once with saturated NaHCO₃ solution and oncewith brine, the resulting organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The crude material was purified by flashchromatography on silica gel with 3:2 Hexane:EtOAc to afford a yellowoil (1.4 g) which was added to piperidine (5 mL), followed by NaI (100mg). The mixture was heated at 70° C. overnight then concentrated invacuo and extracted between EtOAc and saturated NaHCO₃ solution, theorganic layer was washed with brine, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 9:1 EtOAc:MeOHto afford a yellow oil. MS: 290 (M+1). Calc'd. for C₁₅Hl₁₉N₃O₃—289.33.

Step B—Preparation of 1-(2-piperidylethyl)indoline-6-ylamine

[1468] 1-(6-Nitroindolinyl)-2-piperidylethan-1-one (1.6 g, Step A) wasdissolved in 100 mL MeOH, the mixture was bubbled with N₂ for 10 min.10% Pd/C (200 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo to afford a yellow solid. 400 mg was dissolved in 20 mL anhydrousTHF, 5 mL borane-THF (1 M) solution was added dropwise and the mixturewas stirred at RT overnight. The mixture was quenched with MeOH, 100 mgNaOH added and heated at 70° C. for 30 min. The resulting mixture wasconcentrated in vacuo and extracted between EtOAc and saturated NaHCO₃solution, the organic layer was washed with brine, the resulting organiclayer was dried over MgSO₄, filtered and concentrated in vacuo to afforda yellow oil. MS: 246 (M+1). Calc'd. for C₁₅H₂₃N₃—246.36.

Step C—Preparation ofN-[l-(2-piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1469] The titled compound was prepared from1-(2-piperidylethyl)indoline-6-ylamine (Step B) by the method describedin Example 82. MS: 457 (M+1). Calc'd. for C₂₇H₃₂N₆O—456.58.

EXAMPLE 131

[1470]

[1471] MS: 471 (M+1). Calc'd. for C₂₇H₃₀N₆O₂—470.57.

EXAMPLE 132

[1472]

Step A—Preparation of N-(2-bromo-5-nitrophenyl)acetamide

[1473] 2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH₂Cl₂,DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). Themixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mLCH₂Cl₂) was added dropwise to the reaction mixture. After the mixturewas stirred at RT over 3 h, extracted once with saturated NaHCO₃solution and once with brine, the resulting organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a whitesolid. MS: 258 (M−1). Calc'd. for C₈H₇BrN₂O₃—259.06.

Step B—Preparation ofN-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

[1474] A suspension of 2 g NaH (95% powder) in anhydrous DMF (100 mL)was cooled to -78° C., N-(2-bromo-5-nitrophenyl)acetamide (7 g, Step A)in dry DMF (50 mL) was added to the mixture under N₂ atmosphere. Afterthe mixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20dry DMF) was added to the mixture. The mixture was stirred at RTovernight. Next morning, the mixture was poured into a container of iceand extracted between saturated NaHCO₃ solution and EtOAc. The resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 7:2 hexane:EtOAc to afford the title compound as a yellow gum. MS:314 (M+1). Calc'd. for C₁₂H₁₃BrN₂O₃—313.15.

Step C—Preparation of1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

[1475] N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5g, Step B) was dissolved in anhydrous DMF (50 mL), tetraethyl-ammoniumchloride (2.5 g), sodium formate (1.2 g), NaOAc (3 g) were added, andthe resulting mixture was bubbled with N₂ gas for 10 min. Pd(OAc)₂ (350mg) was added and the mixture was heated at 80° C. under N₂ atmosphereovernight. After the mixture was concentrated in vacuo, it waspartitioned between saturated NaHCO₃ solution and EtOAc, the resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 2:1 Hexane:EtOAc to afford the title compound as a yellow gum. MS:235 (M+1). Calc'd. for C₁₂H₁₄N₂O₃—234.25.

Step D—Preparation of 3,3-dimethyl-6-nitroindoline

[1476] 1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g,Step C) was dissolved in EtOH (50 mL), 12N HCl (50 mL) was added and theresulting mixture was heated at 70° C. overnight. After the mixture wasconcentrated in vacuo, it was partitioned between saturated NaHCO₃solution and EtOAc, the resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow solid. MS: 193(M+1). Calc'd. for C₁₀H₁₂N₂O₂—192.21.

Step E—Preparation of3,3-dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole

[1477] 3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in CH₂Cl₂ (50mL), N-methyl-4-piperidone (1 g) was added to the mixture, followed by2.5 g NaBH(OAc)₃ and glacial AcOH (1 mL). The mixture was stirred at RTovernight. Saturated NaHCO₃ solution (50 ml) was added to the reactionmixture and stirred for 1 h. The resulting mixture was separated byseparation funnel, the organic layer was extracted once with saturatedNaHCO₃ solution and once with brine, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 9:1 EtOAc:MeOHto afford the title compound as an orange oil. MS: 290 (M+1). Calc'd.for C₁₆H₂₃N₃O₂—289.37.

Step F—Preparation of3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine

[1478]3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole(600 mg, Step E) was dissolved in MeOH (20 mL), the mixture was bubbledwith H₂ for 10 min. 10% Pd/C (100 mg) was added and the mixture wasstirred under H₂ overnight. The mixture was filtered through Celitee andconcentrated in vacuo to afford the title compound as an oil. MS: 260(M+1). Calc'd. for C₁₆H₂₅N₃13 259.39.

Step G—Preparation ofN-[3,3-dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1479] The titled compound was prepared from3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine (Step E) by themethod described in Example 82. MS: 471 (M+1). Calc'd. forC₂₈H₃₄N₆O—470.61.

EXAMPLE 133

[1480]

Step A—Preparation of 1-acetyl-6-amino-3,3-dimethylindoline

[1481] 1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved inMeOH (20 mL), the mixture was bubbled with H₂ for 10 min. 10% Pd/C (50mg) was added and the mixture was stirred under H₂ overnight. Themixture was filtered through Celite® and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel with1:1 EtOAc:CH₂Cl₂ to afford the title compound as a white crystallinematerial. MS: 205 (M+1). Calc'd. for C₁₂H₁₆N₂O—204.27.

Step B—Preparation ofN-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1482] The titled compound was prepared from1-acetyl-6-amino-3,3-dimethylindoline (Step A) by the method describedin Example 82.

Step C—Preparation ofN-(3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1483] The titled compound was prepared fromN-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(Step B) by the deacylation method described in Example 993. MS: 374(M+1). Calc'd. for C₂₂H₂₃N₅O—373.45.

EXAMPLE 134

[1484]

Step A—Preparation of3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole

[1485] 5-Nitroindole (2.6 g) was dissolved in anhydrous MeOH (100 ml),followed by N-methyl-4-piperidone (5 g) and NaOMe powder (5 g). Themixture was heated to reflux under N₂ overnight. The mixture wasconcentrated in vacuo. The crude was partitioned between saturatedNaHCO₃ solution and EtOAc, the resulting organic layer was dried overMgSO₄, filtered and concentrated in vacuo to afford a yellow solid. Thissolid was washed with EtOAc (5 mL) and MeOH (2 ml) to afford the titlecompound as a bright yellow solid. MS: 258 (M+1). Calc'd. forC₁₄H₁₅N₃O₂—257.29.

Step B—Preparation of 3-(1-methyl-4-piperidyl)indole-5-ylamine

[1486] 3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole(2.7 g, Step A) was dissolved in MeOH (50 mL), the mixture was bubbledwith H₂ for 10 min. 10% Pd/C (150 mg) was added and the mixture wasstirred under H₂ overnight. The mixture was filtered through Celite® andconcentrated in vacuo to afford 3-(1-methyl-4-piperidyl)indole-5-ylamineas a yellow oil. MS: 230 (M+1). Calc'd. for C₁₄H₁₉N₃—229.32.

Step C—Preparation ofN-[3-(1-methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1487] The titled compound was prepared from3-(1-methyl-4-piperidyl)indole-5-ylamine (Step B) by the methoddescribed in Example 82. MS: 441 (M+1). Calc'd. for C₂₆H₂₈N₆O—440.54.

EXAMPLE 135

[1488]

Step A—Preparation of methyl 2-methyl-2-(4-nitrophenyl)propionate

[1489] To a stirred solution of 2-(4-nitrophenyl)-propionic acid (9 g,46 mmol) in MeOH (300 mL) was added HCl (4M in dioxane, 11.5 mL, 46mmol). The mixture was stirred at RT overnight and quenched with aqueousNaHCO₃. The mixture was extracted with EtOAc. The organic layer wasdried over MgSO₄, evaporated under reduced pressure and to the partialresidue at 0° C. in THF (100 mL) was added NaH (1.66 g, 41.5 mmol). Themixture was stirred at RT for 1 h and MeI (2.58 g, 41.5 mmol) was added.The reaction was stirred at RT overnight and was quenched with H₂O. Themixture was extracted with EtOAc, the organic layer was dried overMgSO₄, evaporated under reduced pressure to give the title compoundwhich was used in the next step without further purification. Calc'd forC₁₁H₁₃NO₄: 223.08.

Step B—Preparation of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol

[1490] To a stirred solution of methyl2-methyl-2-(4-nitrophenyl)propionate (5.32 g, 23.8 mmol, Step A) in THF(200 mL) at 0° C. was added a solution of BH₃ 1M in THF (25.8 mL, 45.8mmol). The reaction was stirred at RT overnight and quenched with MeOH.THF was evaporated under reduced pressure and the residue was diluted inEtOAc and aqueous 1M HCl was added. The mixture was extracted withEtOAc, the organic layer was dried over MgSO₄ and evaporated underreduced pressure. The product was purified by flash chromatography using40% EtOAc-hexane to give the title compound as a yellow solid.

Step C—Preparation of 2-methyl-2-(4-nitro-phenyl)-propionaldehyde

[1491] To a stirred solution of the alcohol (2.08 g, 10.8 mmol, Step B)at 0° C. in CH₂Cl₂ was added NMO (1.9 g, 16.1 mmol), molecular sieves 4Å and TPAP (76 mg, 0.2 mmol). The reaction was stirred for 1 h and wasfiltered on silica pad. Solvent was evaporated under reduced pressure.Crude aldehyde was used without further purification in the next step.

Step D—Preparation of 3-methyl-3-(4-nitrophenyl)butan-1-aldehyde

[1492] To a suspension of methoxymethyltriphenyl-phosphonium chloride(6.4 g, 18.6 mmol) in THF (150 mL) was added a solution of KHMDS 0.5 Min toluene (37 mL, 18.5 mmol). The mixture was stirred for 30 min andcrude aldehyde (Step C) was added. The reaction was stirred at RT for 1h and quenched with H₂O. Mixture was extracted with EtOAc, dried andevaporated under reduced pressure. Et₂O was added and the formedprecipitate was filtered on silica pad (rinsed with 40% EtOAc-hexane).The solvent was removed and crude product was dissolved in CH₂Cl₂. Asolution of TFA-H₂O (1:1, 10 mL) was added and the reaction was stirredfor 2 h at RT. Aqueous NaHCO₃ was added until pH 7 and residue wasextracted with CH₂Cl₂. Organic layer was dried, filtered and evaporated.Crude compound was purified by flash chromatography (40% EtOAc-hexane)to give the title compound as a yellow oil. Calc'd for C₁₁H₁₃NO₃:207.09.

Step E—Preparation of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine

[1493] To a stirred solution of3-methyl-3-(4-nitrophenyl)butan-1-aldehyde (509 mg, 2.4 mmol, Step D)and morpholine (0.21 mL, 2.4 mmol) in THF (30 mL) was added NaBH(OAc)₃(0.73 g, 3.4 mmol). The mixture was stirred at RT overnight and waswashed with 1M HCl. CH₂Cl₂ was added and the layers were separated. Theaqueous layer was basified to pH 9 using 1M NaOH and extracted withCH₂Cl₂. This organic layer was dried and evaporated yielding themorpholino compound. Calc'd for C₁₅H₂₂N₂O₃: 278.16.

Step F—Preparation of 4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine

[1494] To a solution of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine(0.50g, 1.8 mmol, Step E) in THF (40 mL) was added AcOH (1.97 mmol, 34.5mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1h and filtered on Celite®. The mixture was diluted with H₂O, and aqueousNaHCO₃ and the THF was evaporated. The residue was extracted with EtOAc,dried and evaporated to give the title intermediate. Calc'd forC₁₅H₂₄N₂O: 248.19.

Step G—Preparation ofN-[4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1495] The titled compound was prepared from4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine (Step F) by themethod described in Example 82. MS: 460.0 (M+1). Calc'd. forC₂₇H₃₃N₅O₂—459.60.

EXAMPLE 136

[1496]

Step A—Preparation of 4-hydroxymethyl-1-methylpiperidine

[1497] To a solution of 4-piperidylmethanol (1.0 g, 8.7 mmol) and HCHO(2 mL, 25 mmol, 37% in H₂ ₂O) in CH₃CN was added NaCNBH₃ (0.5 g, 12.5mmol). The resulting mixture was stirred for 1 h and filtered. Thefiltrate was concentrated and the residue was distilled (105° C., 40torr) to give the title intermediate.

Step B—Preparation of{2-[(1-methyl4-piperidyl)methoxy]-4-pyridyl}methylamine

[1498] To a suspension of NaH (0.4 4 g, 12.7 mmol, 60% in mineral oil)in DMF (25 mL) was added a solution of alcohol (1.1 g, 8.5 mmol, Step A)in 3 mL of DMF. After 20 min, a solution of 2-chloro-4-cyanopyridine(1.2 g, 8.5 mmol) in 2 mL of DMF was added. The resulting mixture wasstirred for 2 h, diluted with CH₂Cl₂, and washed with H₂O twice. Theorganic layer was dried over Na₂SO₄ and concentrated to give2-[(1-methyl-4-piperidyl)methoxy]pyridine-4-carbonitrile, which washydrogenated under regular conditions to furnish the title intermediate.MS (ES+): 236 (M+H)⁺. Calc'd C₁₃H₂₁N₃O—235.33.

Step C—Preparation ofN-[4-(tert-butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamide

[1499] The title compound was prepared from{2-[(1-methyl-4-piperidyl)methoxy]-4-pyridyl}methylamine (Step B) by themethod described in Example 82. MS (ES+): 488 (M+H)⁺; (ES−): 486 (M−H)⁻.Calc'd C₂₉H₃₇N₅O₂—487.64.

EXAMPLE 137

[1500]

[1501] MS (ES+): 402 (M+H)⁺; (ES−): 400. Calc'd C₁₈H₁₄BrFN₄O—401.238.

EXAMPLE 138

[1502]

[1503] MS (ES+): 395 (M+H)⁺; (ES−): 393(M−H)⁻. Calc'dC₂₂H₂₃ClN₄O—394.90.

EXAMPLE 139

[1504]

[1505] A mixture ofN-[4-(tert-butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide(0.15 g, 0.38 mmol, Example 139), 1-dimethylamino-2-propyne (62 mg, 0.76mmol), PdCl₂(PPh₃)₂ (13 mg, 0.0019 mmol) and CuI (7 mg, 0.019 mmol) in 1mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resultingmixture was filtered over Celite®. The filtrate was concentrated, andthe residue was purified by prep-HPLC (reverse phase) to give the titlecompound. MS (ES+): 442 (M+H)⁺; (ES−): 440(M−H)⁻. Calc'dC₂₇H₃₁N₅O—441.58.

EXAMPLE 140

[1506]

Step A—Preparation of (2-methoxy-4-pyridyl)methylamine

[1507] A solution of 2-methoxyisonicotinylcarboxamide (1.0 g, 6.5 mmol)and BH₃-THF complex (35 mmol) in 35 mL of THF was stirred at RT for 16h. The reaction was quenched by addition of MeOH, and the resultingmixture was concentrated. The residue was diluted with iN aq. NaOH andCH₂Cl₂. The organic layer was separated, dried over Na₂SO₄, andconcentrated.

Step B—Preparation of(2-{[(2-methoxy(4-pyridyl))methyl]-amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide

[1508] The title compound was prepared from(2-methoxy-4-pyridyl)methylamine (Step A) by the method described inExample 82. MS (ES+) 377 (M+H)⁺; (ES−): 375 (M−H)⁻. Calc'dC₂₂H₂₄N₄O₂—376.46.

EXAMPLE 141

[1509]

Step A—Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propyn-2-yl}dimethylamine

[1510] A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol),1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl₂(PPh₃)₂ (0.26 g,0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at100° C. in a sealed tube for 3 h. The resulting mixture was filteredover Celite®. The filtrate was concentrated, and the residue waspurified by prep-HPLC (reverse phase) to give the titled compound. MS(ES+): 243 (M+H)⁺; (ES−):241 (M−H)⁻. Calc'd C₁₂H₁₃F₃N₂—242.24.

Step B—Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propyl}dimethylamine

[1511] A mixture of the propynyl-aniline (7 g, 29 mmol, Step A) andPd(OH)₂ (0.5 g) in MeOH (250 mL) was stirred under 50 psi H₂. After 2 h,the resulting mixture was filtered over Celite®. The filtrate wasconcentrated, and the residue was diluted with aq. 1N HCl. The aq. layerwas washed with Et₂O, made basic with aq. 5N NaOH, and extracted withCH₂Cl₂. The organic solution was dried over NaSO₄ and concentrated togive the titled compound. MS (ES+): 386 (M+H)⁺; (ES−): 384 (M−H)⁻.Calc'd C₁₈H₁₉ClF₃N₃O—385.81.

Step C—Preparation ofN-{3-[3-(dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1512] The title compound was prepared by the method described inExample 82. MS (ES+): 458(M+H)⁺; (ES−): 456(M−H)⁻. Calc'dC₂₄H₂₆F₃N₅O—457.497.

EXAMPLE 142

[1513]

Step A—Preparation of 1-piperidylprop-2-en-1-one

[1514] To a 0° C. solution of acryloyl chloride (4.576 g, 50.558 mmol)in 50 ml of CH₂Cl₂ was added dropwise and very carefully piperidine(4.305 g, 50.558 mmol). The reaction flask was vented during theexothermic addition. After the addition was completed, the white slurrywas stirred at 0° C. for 40 min and at RT for 1 h. The reaction wasdiluted with 70 ml CH₂Cl₂ and washed first with about 60 ml 2N HCl andthen with about 60 ml of a mix of 2N NaOH and brine. The organic layerwas dried over Na₂SO₄. The solution was evaporated by heating in a H₂Obath at 60° C. without vacuum. Once most solvent had been evaporatedoff, it was furthered dried to a clear oil under high vacuum at RT for30 min.

Step B—Preparation of 1-bromo-2-(tert-butyl)-5-nitrophenyl

[1515] Br₂ (17.4 ml) was added dropwise over 40 min to a stirred mixtureof 4-tert-butylnitrobenzene (59.5 g, 332 mmol), AgSO₄ (56.5 g, 181mmol), H₂SO₄ (300 ml), and H₂O (33 ml) at RT. The mixture was stirredfor 3 h, then poured into 0.1 M Na₂S₂O₅/H₂O (1 L). The solid wasfiltered, washed with H₂O, Et₂O, and CH₂Cl₂. The filtrate layers wereseparated. The aqueous fraction was extracted with Et₂O. The combinedorganic layers were combined, dried over Na₂SO₄, and concentrated invacuo. The yellow solid was triturated with hexanes to give a paleyellow crystalline solid.

Step C—Preparation of(2E)-3-[2-(tert-butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one

[1516] 1-(tert-Butyl)-2-bromo-4-nitrobenzene (6.885 g, 26.674 mmol, StepB), 1-piperidylprop-2-en-1-one (4.827 g, 34.677 mmol, Step A), and TEA(7.44 ml, 53.35 mmol) were dissolved into toluene (70 ml). To thissolution was added Pd(OAc)₂ (60 mg, 0.267 mmol) and Pd(PPh₃)₄ (617 mg,0.5335 mmol). The mix was degassed with N₂ and heated in a sealed vesselat 120° C. for 15 h. The reaction mixture was cooled to RT, filtered,and concentrated in vacuo. The dark crude oil was eluted through asilica gel column with 15% to 22% EtOAc/hexanes gradient system to yielda thick amber oil as the title intermediate.

Step D—Preparation of(2E)-3-[2-(tert-butyl)-5-aminophenyl]-1-piperidylprop-2-en-1-one

[1517] (2E)-3-[2-(tert-Butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one(3.22 g, 10.177 mmol, step C) was dissolved in dioxane (20 ml) and IpOH(40 ml). To the N₂-degassed solution was added 10% by weight Pd/Ccatalyst (2 g). The mix was placed into a Parr hydrogenator and stirredfor 18 h under 60 psi H₂. The reaction was not complete the next day, sothe reaction was continued for an additional 20 h with fresh catalyst.The mix was filtered through Celite® and concentrated in vacuo to give afoamy oil.

Step E—Preparation of 4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine

[1518] (2E)-3-[2-(tert-Butyl)-5-aminophenyl]-1-piperidylprop-2-en-1-one(2.312 g, 7.619 mmol, step D) was dissolved in THF (100 ml) at RT. Tothis solution was added LiAlH₄ (434 mg, 11.43 mmol). After the reactionmixture stopped exotherming, it was heated at reflux at about 80° C. for4 h. The reaction was cooled to 0° C. and treated by dropwise additionof 0.458 ml H₂O, 0.730 ml 10% aqueous NaOH, and 1.19 ml H₂O,respectively. The mix was stirred at RT for 40 min. Na₂SO₄ (3 g) wasadded and the mix was stirred for 20 min. The mix was filtered throughCelite® and concentrated in vacuo. The crude was eluted through silicagel column with a gradient system of 95:5 to 90:10 CH₂Cl₂:MeOH, to yieldan amber thick oil as the title compound.

Step F—Preparation ofN-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1519] The title compound was prepared from4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine (Step E) similar to themethod described in Example 82. MS: 486.2 (M+1). Calc'd. forC₃₀H₃₉N₅O—485.68.

EXAMPLE 143

[1520]

[1521] MS: 472.5 (M+1). Calc'd. for C₂₉H₃₇N₅O—471.65.

EXAMPLE 144

[1522]

[1523] MS: 484.0 (M+1). Calc'd. for C₃₀H₃₇N₅O—483.66.

EXAMPLE 145

[1524]

[1525] MS: 488.4 (M+1). Calc'd. for C₂₉H₃₇N₅O₂—487.65.

EXAMPLE 146

[1526]

Step A—Preparation of 1-(2-morpholin-4-ylethyl)indole-6-ylamine

[1527] K₂CO₃ (5.08 g, 36.726 mmol) was added to a slurry of6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl)morpholinehydrochloride (2.278 g, 12.242 mmol), and CH₃CN (100 ml). The mix washeated at reflux for 18 h, then cooled to RT, filtered, and concentratedin vacuo. The crude was eluted through a silica gel column with agradient of 3:97 to 5:95 and finally 8:92 MeOH:CH₂Cl₂, to yield upondrying 1-(2-morpholin-4-yl-ethyl)-6-nitro-1H-indole which washydrogenated at regular condition described early to yield the titlecompound.

Step B—Preparation ofN-[l-(2-morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1528] The title compound was prepared from1-(2-morpholin-4-ylethyl)indole-6-ylamine (Step A) similar to the methoddescribed in Example 82. MS: 457.3 (M+1). Calc'd. for C₂₆H₂₈N₆O₂—456.55.

EXAMPLE 147

[1529]

Step A—Preparation of pyrimidine-4-yl formaldehyde

[1530] Pyrimidine-4-yl formaldehyde was prepared from 4-methylpyrimidine through a reference described in M. C. Liu et al., J MedChem., 1995, 38 (21), 4234-4243.

Step B—Preparation ofN-[4-(tert-butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide

[1531] The title compound was prepared from pyrimidine-4-yl formaldehyde(Step A) similar to the method described in Example 82. MS (ES+):362(M+H);(ES−): 360(M−H). Calc'd. for C₂₁H₂₃N₅O—361.19.

EXAMPLE 148

[1532]

[1533] MS (ES+): 340 (M+H); (ES−): 338 (M−H). Calc'd. forC₁₇H₁₄ClN₅O—339.09.

EXAMPLE 149

[1534]

[1535] MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd. forC₁₈H₁₄F₃N₅O—373.12.

EXAMPLE 150

[1536]

Step A—Preparation of ethyl2-methylthio-4-[benzylamino]pyrimidine-5-carboxylate

[1537] A solution of ethyl4-chloro-2-methylthio-pyrimidine-5-carboxylate (2.8 g, 12.2 mmol) and4-aminomethylpyridine (1.24 mL, 12.2 mmol) in EtOH (20 mL) was heated at70° C. for 2 h. The resulting suspension was concentrated, and theresidue was purified by SiO₂ chromatography to give ethyl2-methylthio-4-[benzylamino]pyrimidine-5-carboxylate. MS (ES+): 305(M+H)⁺; (ES−): 303 (M−H)⁻. Calc'd C₁₅H₁₇N₃O₂S: 303.38.

Step B—Preparation ofN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide

[1538] To a solution of ethyl2-methylthio-4-[benzylamino]-pyrimidine-5-carboxylate (0.1 g, 0.3 mmol,Step A) in EtOH (3 mL) was added 1 mL of aq. 1N NaOH solution. Theresulting mixture was stirred at 45° C. for 2 h. The resulting mixturewas neutralized with aq. 1N HCl and concentrated. To the residue in 3 mLof CH₂Cl₂ was added 4-isopropylaniline (90 mg, 0.66 mmol), HATU (0.18 g,0.45 mmol), and 0.5 mL of TEA (0.36 g, 3.5 mmol). The resulting mixturewas stirred at RT for 4 h and diluted with CH₂Cl₂. The organic solutionwas washed with H₂O, dried over Na₂SO₄ and concentrated. The residue waspurified by SiO₂ chromatography to giveN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide.MS (ES+): 394 (M+H)⁺; (ES−): 392 (M−H)⁻. Calc'd C₂₁H₂₃N₅OS—393.51.

Step C—Preparation ofN-[{4-(isopropyl)phenyl](4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide

[1539] A mixture ofN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide(50 mg, 0.13 mmol, Step B) and Raney-Ni in EtOH (10 mL) was heated atreflux for 2 h. The resulting mixture was filtered, and the filtrate wasconcentrated to give the titled compound. MS (ES+): 348 (M+H)⁺; (ES−):346 (M−H)⁻. Calc'd C₂₀H₂₁N₅O—347.42.

EXAMPLE 151

[1540]

Step A—Preparation of2-{2-[2-(dimethylamino)ethoxy]ethoxy}pyridine-4-carbonitrile

[1541] To a DMF (30 mL) solution of2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH(60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50°C. for 2 h. The warm sodium alkoxide solution was added to2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After theaddition, the reaction mixture was heated to 70° C. for 2 h, then DMFwas removed in vacuo. The residue was partitioned between CH₂Cl₂/H₂O.The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give a light yellow oil (5.6 g). MS: 236 (M+1).Calc'd. for C₁₂H₁₇N₃O₂—235.29.

Step B—Preparation of(2-{2-[4-(aminomethyl)(2-pyridyloxy)]ethoxy}ethoxy)dimethylamine

[1542] 2-{2-[2-(Dimethylamino)ethoxy]ethoxy}pyridine-4-carbonitrile (330mg 1.4 mmol, Step A) was dissolved in EtOH (10 mL) along with TEA (2 mL)and suspended with Pd/C (10%, 40 mg). The reaction mixture was stirredovernight at RT under balloon filled with H₂. After removing theballoon, the reaction suspension was filtered through a layer ofCelite®. The Celite® layer was rinsed with MeOH. The combined filtratewas concentrated in vacuo to give a light yellow oil. MS: 240 (M+1).Calc'd. for C₁₂H₂₁N₃O₂—239.32.

Step C—Synthesis of 2-fluoropyridine-3-carboxylic acid

[1543] To a solution of 2-fluoropyridine (10 g, 100 mmol) in THF (150mL) under −78° C. was dropwise added an LDA solution (2M inheptane/THF/ethylbenzene, 60 mL). The mixture was stirred at −78° C. for3 h after the addition of LDA then quenched with N₂ dried solid CO₂.After warming to RT, the reaction was partitioned between EtOAc (100 mL)and H₂O (200 mL). The aqueous layer was acidified to pH between 3-4 andextracted with EtOAc. The organic solution was collected and washed withbrine and dried over Na₂SO₄. After removing solvent in vacuum, a brownoil was received as the desired compound. MS: 140 (M−H). Calc'd. forC₆H₄FNO₂—141.10.

Step D—Synthesis of 2-fluoropyridine-3-carbonyl chloride

[1544] 2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended inSOCl₂ (100 mL). After heating under reflux for 2 h, the mixture becamehomogeneous. Excess SOCl₂ was removed in vacuo to afford a brown solidas desired product.

Step E—Synthesis ofN-[4-(tert-butyl)phenyl]2-fluoropyridine-3-carboxamide

[1545] To a suspension of 2-fluoropyridine-3-carbonyl chloride (3.2 g,20 mmol, Step D) and NaHCO₃ (4 g, 48 mmol) in CH₂Cl₂ added in dropwise asolution of 4-tert butylaniline (3.0 g, 20 mmol). After the addition,the suspension was stirred at RT for 5 h. Solid inorganic salts wereremoved via filtration. The filtrate was concentrated to afford a brownsolid as desired compound. MS: 273 (M+H). Calc'd. for C₁₆H₁₇FN₂O—272.33.

Step F—Synthesis of{2-[({2-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-4-pyridyllmethyl)amino](3-pyridyl)}-N-(4-tert-butylphenyl)carboxamide

[1546] N-[4-(tert-Butyl)phenyl] 2-fluoropyridine-3-carboxamide (544 mg,2 mmol, Step E) was dissolved in pyridine (5 mL) along with(2-{2-[4-(aminomethyl)(2-pyridyloxy)]ethoxy}ethoxy)dimethylamine (570mg, 2.38 mmol, Step A). The reaction was heated to 85° C. for 48 h.After removal of pyridine in vacuo, the residue was dissolved in CH₂Cl₂and washed with NaHCO₃ (Sat. aq), then brine. After drying over Na₂SO₄,the CH₂Cl₂ solution was concentrated in vacuo and purified via prep.HPLC (H₂O/CH₃CN: 5%-95% gradient) to give the title product. MS: 492(M+1). Calc'd. for C₂₈H₃₇N₅O₃—491.63

[1547] The following compounds (Examples 152-157) were analogouslysynthesized by the method described in Example 151 unless specificallydescribed. Detailed intermediate preparations are included.

EXAMPLE 152

[1548]

Step A—Preparation of4-[2,2,2-trifluoro-1-(2-piperidin-1-yl-ethoxy)-1-trifluoromethyl-ethyl]-phenylamine

[1549] DEAD (366 mg, 2.1 mmol) was added drop-wise to the solution of2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (520 mg, 2 mmol),2-piperidylethan-1-ol (260 mg, 2 mmol) and PPh₃ (550 mg, 2.1 mmol) inTHF (10 mL). The mixture was stirred for 2 h. The reaction waspartitioned between EtOAc and aqueous NaHCO₃ solution and the organicphase was washed with brine. After concentrated in vacuo, the organicresidue was purified by flash chromatography on silica to give the titleintermediate.

Step B—Preparation of{2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide

[1550] The title compound was synthesized by the method described inExample 151. MS: 582 (M+1). Calc'd. for C₂₈H₂₉F₆N₅O₂—581.56.

EXAMPLE 153

[1551]

Step A—Preparation of 2,6-difluoropyridine-3-carbonyl chloride

[1552] The title compound was prepared similar to that described inExample 151, Step D.

Step B—Preparation of(2-{[(2-{2-[2-(dimethylamino)-ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

[1553] The title compound was synthesized by the method described inExample 151. MS: 522 (M+1). Calc'd. for C₂₅H₂₇F₄N₅O₃—521.51.

EXAMPLE 154

[1554]

Step A—Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide

[1555] A solution of 2,6-difluoropyridine-3-carboxylic acid (3.2 g, 20mmol), t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8g, 40 mmol), and DIEA (8 mL) in CH₂Cl₂ (80 mL) was stirred at RT for 1h. The mixture was washed with aq. NaHCO₃ and brine. The organicsolution was dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified via flash chromatography on silica (Hex:EtOAc=4:1) to givea light yellow flaky crystal as desired product.

Step B—Preparation ofN-[4-(tert-butyl)phenyl](6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

[1556] The title compound was synthesized similar to that described inExample 151 except that it was synthesized at RT. MS: 379 (M+1). Calc'd.for C₂₂H₂₃FN₄O—378.45.

[1557] The following compounds were analogously synthesized by themethod described in Example 154. Detailed intermediate preparations aredescribed.

EXAMPLE 155

[1558]

[1559] MS: 365 (M+1). Calc'd. for C₂₁H₂₁FN₄O—364.42.

EXAMPLE 156

[1560]

[1561] MS: 391 (M+1). Calc'd. for C₁₉H₁₄F₄N₄O—390.34.

EXAMPLE 157

[1562]

[1563] MS: 452/454 (M+1). Calc'd. for C₂₁H₁₅BrFN₅O—452.29.

EXAMPLE 158

[1564]

Step A—Preparation of(2-chloro(3-pyridyl))-N-(4-phenoxy-phenyl)carboxamide

[1565] 2-Chloronicotinic acid (0.78 g, 5.0 mmol) and TEA (1.6 ml, 10.0mmol) were added to anhydrous THF (50 ml) under a N₂ atmosphere at 0° C.After stirring for 5 min, ethyl chloroformate (0.54 g, 5.0 mmol) wasadded dropwise and the mixture gradually came to RT over a period of 1h. 4-Phenoxyaniline (0.83 g, 5.0 mmol) was added and the mixture wasstirred for 14 h. The mixture was partitioned between H₂O and EtOAc. Theaqueous layer was extracted two additional times with EtOAc (50 ml). Thecombined organic layers were then washed with brine, dried over Na₂SO₄,and evaporated. The resulting brown oil was used directly in thesubsequent reaction without further purification. MS m/z: 325 (M+1).Calc'd for C₁₈H₁₃ClN₂O₂: 324.07.

Step B—Preparation ofN-(4-phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

[1566] The amide (0.500 g, 1.5 mmol, Step A) and 4-aminomethylpyridine(0.486 g, 4.5 mmol) were combined and heated neat at 90° C. for 48 h.After cooling to RT, the mixture was poured into a saturated NaHCO₃solution and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, and evaporated. The resultingbrown oil was purified by column chromatography with EtOAc/hexanes (2:1)as eluant to leaveN-(4-phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide as aclear oil. This material was converted directly into the HCl salt bydissolution in MeOH (5 ml), treatment with 3 equivalents of an HClethereal solution, and evaporation of solvent to leave the titledproduct as a light yellow solid. MS (ES+): 397 (M+H)⁺; (ES−): 395 (M−H).Calc'd. for C₂₄H₂₀N₄O₂—396.16.

[1567] The following compounds (Examples 159-161) were prepared similarto the method described in Example 158.

EXAMPLE 159

[1568]

[1569] MS: 381 (M+1); 379 (M−1). Calc'd. for C₂₄H₂₀N₄O—380.16.

EXAMPLE 160

[1570]

[1571] MS: 397 (M+1) ; 395 (M−1) . Calc'd. for C₂₄H₂₀N₄O₂—396.16.

EXAMPLE 161

[1572]

[1573] MS: 387 (M+1); 385 (M−1) Calc'd. for C₂₄H₂₆N₄O—386.21.

EXAMPLE 162

[1574]

Step A—Preparation of(2-Chloro(3-pyridyl))-N-(4-imidazolylphenyl)carboxamide

[1575] A slurry of 4-imidazolylphenylamine (15.9 mg, 0.100 mmol),polymer-supported DIPEA (0.100 g, 0.362 mmol , 3.62 mmol/g loading) inCH₂Cl₂ (2 ml) was treated with a 2-chloropyridine-3-carbonyl chloridesolution (0.10 M, 0.200 mmol, 2.0 ml, 2.0 eq) in CH₂Cl₂. The mixture wasvortexed at RT for 14 h. Afterwards, the excess acid chloride wasremoved by treating the reaction mixture with polymer-supportedtrisamine resin (0.100 g, 0.375 mmol, 3.75 mmol/g loading). The slurrywas shaken at RT for an additional 18 h. The reaction mixture wasfiltered, rinsed with CH₂Cl₂ (1 ml), and the filtrate was concentratedunder reduced pressure. The resulting brown oil was used directly in thesubsequent reaction.

Step B—Synthesis ofN-(4-imidazolylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

[1576] (2-Chloro-(3-pyridyl))-N-(4-imidazolylphenyl)-carboxamide wastreated with 4-aminomethylpyridine (0.100 g, 0.93 mmol) and heated neatat 120° C. for 18 h. After cooling to RT, the material was purified bypreparative HPLC. The final product was converted into an HCl salt bydissolution in a minimum of MeOH, treatment with an HCl etherealsolution, and evaporation of solvent. MS: (ES+) 371 (M+1)⁺; (ES−) : 369(M−1)⁻. Calc'd. for C₂₁H₁₈N₆O—370.15.

[1577] The following compounds (Examples 163-166) were analogouslysynthesized by the method described in Example 162.

EXAMPLE 163

[1578]

[1579] The title compound was isolated as the HCl salt. MS: 390 (M+1);388 (M−1). Calc'd. for C₂₂H₂₃N₅O₂—389.19.

EXAMPLE 164

[1580]

[1581] The title compound was isolated as the HCl salt. MS: 380 (M+1);378 (M−1). Calc'd. for C₂₃H₁₇N₅O—379.14.

EXAMPLE 165

[1582]

[1583] The title compound was isolated as the HCl salt. MS: 373 (M+1);371 (M−1). Calc'd. for C₁₉H₁₅F₃N₄O—372.12.

EXAMPLE 166

[1584]

[1585] The title compound was isolated as the HCl salt. MS: 363 (M+1);361 (M−1). Calc'd. for C₂₀H₁₈N₄O₃—362.14.

[1586] The following compounds were synthesized by a procedure similarto the method described in Example 3, using an aldehyde to react withthe aminopyridine core via reductive amination.

EXAMPLE 167

[1587]

[1588] MS: (ES+) 397 (M+H); (ES−) 395 (M−H). Calc'd. forC₂₅H₂₄N₄O—396.20.

EXAMPLE 168

[1589]

[1590] MS (ES+) : 411 (M+H); (ES−) : 409 (M−H) Calc'd. forC₂₆H₂₆N₄O—410.51.

EXAMPLE 169

[1591]

[1592] MS (ES+): 423 (M+H); (ES−): 421 (M−H). Calc'd. for C₂₃H₁₇F₃N₄O:422.14.

[1593] Other compounds included in this invention are set forth inTables 3-9 below. TABLE 3

# R¹ R² n 170. 2-chlorophenyl H 1 171. 4-benzimidazolyl H 1 172.5-benzimidazolyl H 1 173. 7-benzimidazolyl H 1 174. 2-chlorophenyl 5-Br1 175. 3-isoquinolinyl 5-Br 1 176. 2-quinolinyl 5-Br 1 177.2-benzthiazolyl 5-Br 1 178. 2-benzimidazolyl 5-Br 1 179.4-benzimidazolyl 5-Br 1 180. 5-benzimidazolyl 5-Br 1 181.6-benzimidazolyl 5-Br 1 182. 7-benzimidazolyl 5-Br 1 183. 4-chlorophenylH 3 184. 4-chlorophenyl 3-pyridyl 1 185. 4-pyridyl H 1 186. 4-pyridyl6-CH₃ 1 187. 4-chlorophenyl- 5-Cl 1 188. 3,4-dichlorophenyl- 5-Br 1 189.4-fluorophenyl 6-CH₃ 1 190. 3-chlorophenyl 6-CH₃ 1 191. 3-fluorophenyl6-CH₃ 1 192. 3-fluoro-4-methoxyphenyl 6-CH₃ 1 193.3-fluoro-4-methylphenyl 6-Cl 1 194. 4-phenoxyphenyl H 1 195.3-phenoxyphenyl H 1 196. 4-biphenyl H 1 197. 4-cyclohexylphenyl H 1 198.2-quinolyl H 1 199. 3-isoquinolyl H 1 200. 3-quinolyl H 1 201.1-isoquinolyl H 1 202. 5-quinolyl H 1 203. 5-isoquinolyl H 1 204.6-quinolyl H 1 205. 6-isoquinolyl H 1 206. 7-quinolyl H 1 207.7-isoquinolyl H 1 208. 4-quinolyl H 1 209. 4-isoquinolyl H 1 210.4-pyridyl H 1 211. 4-pyrimidinyl H 1 212. 2-pyrimidinyl H 1 213.6-pyrimidinyl H 1 214. 4-pyridazinyl H 1 215. 5-pyridazinyl H 1 216.4-indolyl H 1 217. 5-isoindolyl H 1 218. 5-naphthyridinyl H 1 219.6-quinozalinyl H 1 220. 6-isoquinolyl H 1 221. 4-naphthyridinyl H 1 222.5-quinozalinyl H 1 223. 4-naphthyridinyl H 1 224. 7-tetrahydroquinolinylH 1 225. 6-indazolyl H 1 226. 6-isoindolyl H 1 227. 5-indazolyl H 1 228.5-isoindolyl H 1 229. 6-benzothienyl H 1 230. 6-benzofuryl H 1 231.5-benzothienyl H 1 232. 5-benzofuryl H 1 233. 2-benzimidazolyl H 1 234.2-benzoxazolyl H 1 235. 2-benzthiazolyl H 1 236. 6-benzimidazolyl H 1237. 6-benzoxazolyl H 1 238. 6-benzthiazolyl H 1 239. 2-quinazolinyl H 1240. 3-(phenoxy)-6-pyridyl H 1 241. 4-(phenylcarbonyl)phenyl H 1 242.4-(phenylamino)phenyl H 1 243. 4-cyclohexyloxyphenyl H 1 244.4-(3-thienyl)phenyl H 1 245. 4-(pyrazol-3-yl)phenyl H 1 246.4-chlorophenyl 6-F 2 247. 4-pyridyl 6-Cl 1 248. 3-methoxyphenyl 6-F 1249. 4-hydroxyphenyl 6-Cl 1 250. 3-hydroxyphenyl H 1 251.2-hydroxyphenyl H 1 252. 4-chlorophenyl 6-F 1 253. 4-phenoxyphenyl 6-F 1254. 4-biphenyl 6-phenyl 1 255. 4-hydroxyphenyl 6-phenyl 1 256.4-cyclohexylphenyl 6-F 1 257. 3-isoquinolyl 6-phenyl 1 258.4-piperidinylmethylphenyl H 1 259. 4-morpholinylmethylphenyl H 1

[1594] TABLE 4 a.

# R¹ 260. 4-chlorophenyl 261. 3,4-dichlorophenyl 262. 4-phenoxyphenyl263. 4-biphenyl 264. 4-cyclohexylphenyl 265. 3-isoquinolyl b.

# R¹ 266. 4-chlorophenyl 267. 3,4-dichlorophenyl 268. 4-phenoxyphenyl269. 4-biphenyl 270. 4-cyclohexylphenyl 271. 3-isoquinolyl c.

# R¹ A⁵ 272. 4-chlorophenyl NH 273. 3,4-dichlorophenyl NH 274.4-phenoxyphenyl NH 275. 4-biphenyl NH 276. 4-cyclohexylphenyl NH 277.3-isoquinolyl NH 278. 4-chlorophenyl O 279. 3,4-dichlorophenyl O 280.4-phenoxyphenyl O 281. 4-biphenyl O 282. 4-cyclohexylphenyl O 283.3-isoquinolyl O 284. 3,4-dichlorophenyl S 285. 4-phenoxyphenyl S 286.4-biphenyl S 287. 4-cyclohexylphenyl S 288. 3-isoquinolyl S d.

# R¹ A⁵ 289. 4-chlorophenyl NH 290. 3,4-dichlorophenyl NH 291.4-phenoxyphenyl NH 292. 4-biphenyl NH 293. 4-cyclohexylphenyl NH 294.3-isoquinolyl NH 295. 4-chlorophenyl O 296. 3,4-dichlorophenyl O 297.4-phenoxyphenyl O 298. 4-biphenyl O 299. 4-cyclohexylphenyl O 300.3-isoquinolyl O 301. 3,4-dichlorophenyl S 302. 4-phenoxyphenyl S 303.4-biphenyl S 304. 4-cyclohexylphenyl S 305. 3-isoquinolyl S e.

# R¹ A⁵ 306. 4-chlorophenyl NH 307. 3,4-dichlorophenyl NH 308.4-phenoxyphenyl NH 309. 4-biphenyl NH 310. 4-cyclohexylphenyl NH 311.3-isoquinolyl NH 312. 4-chlorophenyl O 313. 3,4-dichlorophenyl O 314.4-phenoxyphenyl O 315. 4-biphenyl O 316. 4-cyclohexylphenyl O 317.3-isoquinolyl O 318. 3,4-dichlorophenyl S 319. 4-phenoxyphenyl S 320.4-biphenyl S 321. 4-cyclohexylphenyl S 322. 3-isoquinolyl S f.

# R¹ A⁵ 323. 4-chlorophenyl NH 324. 3,4-dichlorophenyl NH 325.4-phenoxyphenyl NH 326. 4-biphenyl NH 327. 4-cyclohexylphenyl NH 328.3-isoquinolyl NH 329. 4-chlorophenyl O 330. 3,4-dichlorophenyl O 331.4-phenoxyphenyl O 332. 4-biphenyl O 333. 4-cyclohexylphenyl O 334.3-isoquinolyl O 335. 3,4-dichlorophenyl S 336. 4-phenoxyphenyl S 337.4-biphenyl S 338. 4-cyclohexylphenyl S 339. 3-isoquinolyl S g.

# R¹ A⁵ 340. 4-chlorophenyl NH 341. 3,4-dichlorophenyl NH 342.4-phenoxyphenyl NH 343. 4-biphenyl NH 344. 4-cyclohexylphenyl NH 345.3-isoquinolyl NH 346. 4-chlorophenyl O 347. 3,4-dichlorophenyl O 348.4-phenoxyphenyl O 349. 4-biphenyl O 350. 4-cyclohexylphenyl O 351.3-isoquinolyl O h.

# R¹ A⁵ 352. 4-chlorophenyl NCH₃ 353. 3,4-dichlorophenyl NCH₃ 354.4-phenoxyphenyl NCH₃ 355. 4-biphenyl NH 356. 4-cyclohexylphenyl NH 357.4-tert-butylphenyl NCH₃ 358. 4-chlorophenyl O 359. 3,4-dichlorophenyl O360. 4-phenoxyphenyl O 361. 4-biphenyl O 362. 4-cyclohexylphenyl O 363.3-isoquinolyl O

[1595] TABLE 5

# R Y R¹ R² 364. 4-pyridyl —NHSO₂— 4-chlorophenyl H 365. 4-pyridyl—NHSO₂— 4-chlorophenyl 5-Br 366. 4-pyridyl —NHSO₂— 3-chlorophenyl H 367.4-pyridyl —NHSO₂— 3-chlorophenyl 5-Br 368. 4-pyridyl —NHSO₂—4-phenoxyphenyl H 369. 4-pyridyl —NHSO₂— 4-biphenyl H 370. 4-pyridyl—NHSO₂— 3-isoquinolyl H 371. 4-pyridyl —NHSO₂— 3-isoquinolyl 5-Br 372.5-quinolyl —NHSO₂— 4-chlorophenyl H 373. 5-quinolyl —NHSO₂—4-chlorophenyl 5-Br 374. 5-quinolyl —NHSO₂— 3-chlorophenyl H 375.5-quinolyl —NHSO₂— 3-chlorophenyl 5-Br 376. 5-quinolyl —NHSO₂—4-phenoxyphenyl H 377. 6-quinolyl —NHSO₂— 4-biphenyl H 378. 5-quinolyl—NHSO₂— 3-isoquinolyl H 379. 6-quinolyl —NHSO₂— 3-isoquinolyl 5-Br 380.4-pyridyl —NHCH₂—

H 381.

—NHCH₂—

H 382.

—NHCH₂—

H 383.

—NHCH₂—

H 384.

—NHCH₂—

H 385.

—NHCH₂— 4-CF₃-phenyl H 386.

—NHCH₂—

H 387.

—NHCH₂—

H 388.

—NHCH₂—

H 389.

—NHCH₂— 3-CF₃-phenyl H 390.

—NHCH₂—

H 391.

—NHCH₂—

H 392.

—NHCH₂— 4-CF₃-phenyl H 393.

—NHCH₂—

H 394.

—NHCH₂—

H 395.

—NHCH₂—

H 396.

—NHCH₂— 3-CF₃-phenyl H 397.

—NHCH₂—

H 398.

—NHCH₂—

H 399.

—NHCH₂—

H 400.

—NHCH₂— 4-CF₃-phenyl H 401.

—NHCH₂—

H 402.

—NHCH₂—

H 403.

—NHCH₂— 3-CF₃-phenyl H 404.

—NHCH₂—

H 405.

—NHCH₂—

H 406.

—NHCH₂— 4-CF₃-phenyl H 407.

—NHCH₂—

H 408.

—NHCH₂—

H 409.

—NHCH₂—

H 410.

—NHCH₂— 3-CF₃-phenyl H 411.

—NHCH₂—

H 412.

—NHCH₂—

H 413.

—NHCH₂— 4-CF₃-phenyl H 414. 4-pyridyl —NHCH₂—

H 415. 4-pyridyl —NHCH₂—

H 416. 4-pyridyl —NHCH₂—

H 417. 4-pyridyl —NHCH₂—

H 418. 4-pyridyl —NHCH₂—

H 419. 4-pyrimidinyl —NHCH₂—

H 420. 4-pyrimidinyl —NHCH₂—

H 421. 4-pyrimidinyl —NHCH₂—

H 422. 4-pyrimidinyl —NHCH₂—

H 423. 4-pyrimidinyl —NHCH₂—

H 424. 4-pyrimidinyl —NHCH₂—

H 425. 4-pyrimidinyl —NHCH₂—

H 426. 4-pyrimidinyl —NHCH₂—

H 427. 4-pyrimidinyl —NHCH₂—

H 428. 4-pyrimidinyl —NHCH₂—

H 429. 3-pyridyl —NH(CH₂)₂—

H 430. 3-pyridyl —NH(CH₂)₂—

H 431. 3-pyridyl —NH(CH₂)₂—

H 432. 3-pyridyl —NH(CH₂)₂—

H 433. 3-pyridyl —NH(CH₂)₂—

H 434. 3-pyridyl —NH(CH₂)₂—

H 435. 3-pyridyl —NH(CH₂)₂—

H 436. 3-pyridyl —NH(CH₂)₂—

H 437. 3-pyridyl —NH(CH₂)₂—

H 438.

—NHCH₂—

H 439.

—NHCH₂—

H 440.

—NHCH₂—

H 441.

—NHCH₂—

H 442.

—NHCH₂—

H 443.

—NHCH₂—

H 444.

—NHCH₂—

H 445.

—NHCH₂—

H 446.

—NHCH₂—

H 447.

—NHCH₂—

H 448.

—NHCH₂—

H 449.

—NHCH₂—

H 450.

—NHCH₂—

H 451.

—NHCH₂—

H 452.

—NHCH₂—

H 453.

—NHCH₂—

H 454.

—NHCH₂—

H 455.

—NHCH₂—

H 456.

—NHCH₂—

H 457.

—NHCH₂—

H 458.

—NHCH₂—

H 459.

—NHCH₂—

H 460.

—NHCH₂—

H 461.

—NHCH₂—

H 462. 4-pyridyl —NHCH₂—

H 463. 4-pyridyl —NHCH₂—

H 464. 4-pyridyl —NHCH₂—

H 465. 4-pyridyl —NHCH₂—

H 466. 4-pyridyl —NHCH₂—

H 467. 4-pyridyl —NHCH₂—

H 468. 4-pyridyl —NHCH₂—

H 469. 4-pyridyl —NHCH₂—

H 470. 3-pyridyl —NH(CH₂)₂—

H 471. 3-pyridyl —NH(CH₂)₂—

H 472. 3-pyridyl —NH(CH₂)₂—

H 473. 3-pyridyl —NH(CH₂)₂—

H 474. 3-pyridyl —NH(CH₂)₂—

H 475. 3-pyridyl —NH(CH₂)₂—

H 476. 3-pyridyl —NH(CH₂)₂—

H 477. 3-pyridyl —NH(CH₂)₂—

H 478. 3-pyridyl —NH(CH₂)₂—

H 479. 4-pyrimidinyl —NHCH₂—

H 480. 4-pyrimidinyl —NHCH₂—

H 481. 4-pyrimidinyl —NHCH₂—

H 482. 4-pyrimidinyl —NHCH₂—

H 483. 4-pyrimidinyl —NHCH₂—

H 484. 4-pyrimidinyl —NHCH₂—

H 485. 4-pyrimidinyl —NHCH₂—

H 486. 4-pyrimidinyl —NHCH₂—

H 487. 4-pyrimidinyl —NHCH₂—

H 488. 4-pyrimidinyl —NHCH₂—

H 489. 4-pyrimidinyl —NHCH₂—

H 490. 4-pyrimidinyl —NHCH₂—

H 491.

—NHCH₂—

H 492.

—NHCH₂—

H 493.

—NHCH₂—

H 494.

—NHCH₂—

H 495.

—NHCH₂—

H 496.

—NHCH₂—

H 497.

—NHCH₂—

H 498.

—NHCH₂—

H 499.

—NHCH₂—

H 500.

—NHCH₂—

H 501.

—NHCH₂—

H 502.

—NHCH₂—

H 503.

—NHCH₂—

H 504.

—NHCH₂—

H 505.

—NHCH₂—

H 506.

—NHCH₂—

H 507.

—NHCH₂—

H 508.

—NHCH₂—

H 509.

—NHCH₂—

H 510.

—NHCH₂—

H 511.

—NHCH₂—

H 512.

—NHCH₂—

H 513.

—NHCH₂—

H 514.

—NHCH₂—

H 515.

—NHCH₂—

H 516.

—NHCH₂—

H 517.

—NHCH₂—

H 518.

—NHCH₂—

H 519.

—NHCH₂—

H 520.

—NHCH₂—

H 521.

—NHCH₂—

H 522.

—NHCH₂—

H 523.

—NHCH₂—

H 524.

—NHCH₂—

H 525. 4-pyridyl —NHCH₂— 3-CF₃-phenyl H 526. 4-pyridyl —NHCH₂—

H 527. 4-pyridyl —NHCH₂—

H 528. 4-pyridyl —NHCH₂—

H 529. 4-pyridyl —NHCH₂—

H 530. 4-pyridyl —NHCH₂—

H 531. 4-pyridyl —NHCH₂—

H 532. 4-pyridyl —NHCH₂—

H 533. 4-pyridyl —NHCH₂—

H 534. 3-pyridyl —NH(CH₂)₂—

H 535. 3-pyridyl —NH(CH₂)₂—

H 536. 3-pyridyl —NH(CH₂)₂—

H 537. 3-pyridyl —NH(CH₂)₂—

H 538. 3-pyridyl —NH(CH₂)₂—

H 539. 4-pyridyl —NHCH₂—

H 540. 4-pyrimidinyl —NHCH₂—

H 541. 4-pyrimidinyl —NHCH₂—

H 542. 4-pyrimidinyl —NHCH₂—

H 543. 4-pyrimidinyl —NHCH₂—

H 544. 4-pyrimidinyl —NHCH₂—

H 545. 4-pyrimidinyl —NHCH₂—

H 546. 4-pyrimidinyl —NHCH₂—

H 547. 4-pyrimidinyl —NHCH₂—

H 548. 4-pyrimidinyl —NHCH₂—

H 549. 4-pyrimidinyl —NHCH₂—

H 550.

—NHCH₂— 3-CF₃-phenyl H 551.

—NHCH₂—

H 552.

—NHCH₂—

H 553.

—NHCH₂—

H 554.

—NHCH₂—

H 555.

—NHCH₂—

H 556.

—NHCH₂—

H 557.

—NHCH₂— 3-CF₃-phenyl H 558.

—NHCH₂—

H 559.

—NHCH₂—

H 560.

—NHCH₂—

H 561.

—NHCH₂—

H 562.

—NHCH₂—

H 563.

—NHCH₂—

H 564.

—NHCH₂— 3-CF₃-phenyl H 565.

—NHCH₂—

H 566.

—NHCH₂—

H 567.

—NHCH₂—

H 568.

—NHCH₂—

H 569.

—NHCH₂—

H 570.

—NHCH₂—

H 571.

—NHCH₂—

H 572.

—NHCH₂—

H 573.

—NHCH₂—

H 574.

—NHCH₂— 3-CF₃-phenyl H 575.

—NHCH₂—

H 576.

—NHCH₂—

H 577.

—NHCH₂—

H 578.

—NHCH₂—

H 579.

—NHCH₂—

H 580.

—NHCH₂—

H 581. 4-pyrimidinyl —NHCH₂—

H 582. 4-pyrimidinyl —NHCH₂—

H 583. 4-pyrimidinyl —NHCH₂—

H 584.

—NHCH₂—

H 585.

—NHCH₂—

H 586.

—NHCH₂—

H 587.

—NHCH₂—

H 588.

—NHCH₂—

H 589.

—NHCH₂—

H 590.

—NHCH₂—

H 591.

—NHCH₂—

H 592.

—NHCH₂—

H 593.

—NHCH₂—

H 594.

—NHCH₂—

H 595.

—NHCH₂—

H 596.

—NHCH₂—

H 597.

—NHCH₂—

H 598.

—NHCH₂—

H 599.

—NHCH₂—

H 600.

—NHCH₂—

H 601.

—NHCH₂—

H 602.

—NHCH₂— 3-CF₃-phenyl H 603.

—NHCH₂— 4-CF₃-phenyl H 604.

—NHCH₂—

H 605.

—NHCH₂—

H 606.

—NHCH₂—

H 607.

—NHCH₂— 3-CF₃-phenyl H 608.

—NHCH₂—

H 609.

—NHCH₂— 4-CF₃-phenyl H 610.

—NHCH₂—

H 611.

—NHCH₂—

H 612.

—NHCH₂— 3-CF₃-phenyl H 613.

—NHCH₂— 4-CF₃-phenyl H 614.

—NHCH₂—

H 615.

—NHCH₂—

H 616.

—NHCH₂—

H 617.

—NHCH₂—

H 618.

—NHCH₂— 3-CF₃-phenyl H 619.

—NHCH₂— 4-CF₃-phenyl H 620.

—NHCH₂—

H 621.

—NHCH₂—

H 622.

—NHCH₂—

H 623.

—NHCH₂— 3-CF₃-phenyl H 624.

—NHCH₂— 4-CF₃-phenyl H 625. 4-pyridyl —NHCH₂—

H 626.

—NHCH₂—

H 627.

—NHCH₂—

H 628.

—NHCH₂—

H 629.

—NHCH₂—

H 630.

—NHCH₂—

H 631.

—NHCH₂—

H 632.

—NHCH₂—

H 633. 3-pyridyl —NH(CH₂)₂—

H 634. 4-pyrimidinyl —NHCH₂—

H 635. 4-pyridyl —NHCH₂—

H

[1596] TABLE 6

# R¹ n R² 636. 4-chlorophenyl 1 6-F 637. 3,4-dichlorophenyl 1 H 638.4-fluorophenyl 1 H 639. 3-chlorophenyl 1 H 640. 3-fluorophenyl 1 H 641.3-fluoro-4-methoxyphenyl 1 H 642. 3-fluoro-4-methylphenyl 2 H 643.4-phenoxyphenyl 1 H 644. 3-phenoxyphenyl 1 H 645. 4-biphenyl 1 H 646.4-cyclohexylphenyl 1 H 647. 2-quinolyl 1 H 648. 3-isoquinolyl 1 H 649.3-quinolyl 1 H 650. 1-isoquinolyl 1 H 651. 5-quinolyl 1 H 652.5-isoquinolyl 1 H 653. 6-quinolyl 1 H 654. 6-isoquinolyl 1 H 655.7-quinolyl 1 H 656. 7-isoquinolyl 1 H 657. 4-quinolyl 1 H 658.4-isoquinolyl 1 H 659. 4-pyridyl 1 6-F 660. 4-pyrimidinyl 1 H 661.2-pyrimidinyl 1 H 662. 6-pyrimidinyl 1 H 663. 4-pyridazinyl 1 H 664.5-pyridazinyl 1 H 665. 4-indolyl 1 H 666. 5-isoindolyl 1 H 667.5-naphthyridinyl 1 H 668. 6-quinozalinyl 1 H 669. 6-isoquinolyl 1 H 670.4-naphthyridinyl 1 H 671. 5-quinozalinyl 1 H 672. 4-naphthyridinyl 1 H673. tetrahydroquinolinyl 1 H 674. 6-indazolyl 1 H 675. 6-isoindolyl 1 H676. 5-indazolyl 1 H 677. 5-isoindolyl 1 H 678. 6-benzothienyl 1 H 679.6-benzofuryl 1 H 680. 5-benzothienyl 1 H 681. 5-benzofuryl 1 H 682.2-benzimidazolyl 1 H 683. 2-benzoxazolyl 1 H 684. 2-benzthiazolyl 1 H685. 6-benzimidazolyl 1 H 686. 6-benzoxazolyl 1 H 687. 6-benzthiazolyl 1H 688. 2-quinazolinyl 1 H 689. 3-(phenoxy)-6-pyridyl 1 H 690.4-(phenylcarbonyl)phenyl 1 H 691. 4-(phenylamino)phenyl 1 H 692.cyclohexyloxyphenyl 1 H 693. 4-(3-thienyl)phenyl 1 H 694.4-(pyrazol-3-yl)phenyl 1 6-CH₃

[1597] TABLE 7

# R¹ n R² 695. 4-chlorophenyl 1 6-Cl 696. 3,4-dichlorophenyl 1 5-Cl 697.4-fluorophenyl 1 H 698. 3-chlorophenyl 1 H 699. 3-fluorophenyl 1 H 700.3-fluoro-4-methoxyphenyl 1 H 701. 3-fluoro-4-methylphenyl 1 H 702.4-phenoxyphenyl 1 H 703. 3-phenoxyphenyl 1 H 704. 4-biphenyl 1 H 705.4-cyclohexylphenyl 1 H 706. 2-quinolyl 1 H 707. 3-isoquinolyl 1 H 708.3-quinolyl 1 H 709. 1-isoquinolyl 1 H 710. 5-quinolyl 1 H 711.5-isoquinolyl 1 H 712. 6-quinolyl 1 H 713. 6-isoquinolyl 1 H 714.7-quinolyl 1 H 715. 7-isoquinolyl 1 H 716. 4-quinolyl 1 H 717.4-isoquinolyl 1 H 718. 4-pyridyl 1 H 719. 4-pyrimidinyl 1 H 720.2-pyrimidinyl 1 H 721. 6-pyrimidinyl 1 H 722. 4-pyridazinyl 1 H 723.5-pyridazinyl 1 H 724. 4-indolyl 1 H 725. 5-isoindolyl 1 H 726.5-naphthyridinyl 1 H 727. 6-quinozalinyl 1 H 728. 6-isoquinolyl 1 H 729.4-naphthyridinyl 1 H 730. 5-quinozalinyl 1 H 731. 4-naphthyridinyl 1 H732. tetrahydroquinolinyl 1 H 733. 6-indazolyl 1 H 734. 6-isoindolyl 1 H735. 5-indazolyl 1 H 736. 5-isoindolyl 1 H 737. 6-benzothienyl 1 H 738.6-benzofuryl 1 H 739. 5-benzothienyl 1 H 740. 5-benzofuryl 1 H

[1598] TABLE 8

# R¹ n R² 741. 2-benzimidazolyl 1 H 742. 2-benzoxazolyl 1 H 743.2-benzthiazolyl 1 H 744. 6-benzimidazolyl 1 H 745. 6-benzoxazolyl 1 H746. 6-benzthiazolyl6-benzoxazolyl 1 H 747. 2-quinazolinyl6-benzoxazolyl1 H 748. 3-(phenoxy)-6-pyridyl 1 H 749. 4-(phenylcarbonyl)phenyl 1 H750. 4-(phenylamino)phenyl 1 H 751. cyclohexyloxyphenyl 1 H 752.4-(3-thienyl)phenyl 1 H 753. 4-(pyrazol-3-yl)phenyl 1 H 754.4-chlorophenyl 1 EtO₂CCH═CH— 755. 4-chlorophenyl 1 5-Br

# R¹ n R² 756. 4-pyridyl 1 H 757. 4-pyridyl 1 H 758. 4-chlorophenyl 16-F 759. 3,4-dichlorophenyl- 1 6-CH₃ 760. 4-fluorophenyl 1 H 761.3-chlorophenyl 1 H 762. 3-fluorophenyl 1 H 763. 3-fluoro-4-methoxyphenyl1 H 764. 3-fluoro-4-methylphenyl 1 H 765. 4-phenoxyphenyl 1 H 766.3-phenoxyphenyl 1 H 767. 4-biphenyl 1 H 768. 4-cyclohexylphenyl 1 H 769.2-quinolyl 1 H 770. 3-isoquinolyl 1 H 771. 3-quinolyl 1 H 772.1-isoquinolyl 1 H 773. 5-quinolyl 1 H 774. 5-isoquinolyl 1 H 775.6-quinolyl 1 H 776. 6-isoquinolyl 1 H 777. 7-quinolyl 1 H 778.7-isoquinolyl 1 H 779. 4-quinolyl 1 H 780. 4-isoquinolyl 1 H 781.4-pyridyl 1 H 782. 4-pyrimidinyl 1 H 783. 2-pyrimidinyl 1 H 784.6-pyrimidinyl 1 H 785. 4-pyridazinyl 1 H 786. 5-pyridazinyl 1 H 787.4-indolyl 1 H 788. 5-isoindolyl 1 H 789. 5-naphthyridinyl 1 H 790.6-quinozalinyl 1 H 791. 6-isoquinolyl 1 H 792. 4-naphthyridinyl 1 H 793.5-quinozalinyl 1 H 794. 4-naphthyridinyl 1 H 795. 7-tetrahydroquinolinyl1 H 796. 6-indazolyl 1 H 797. 6-isoindolyl 1 H 798. 5-indazolyl 1 H 799.5-isoindolyl 1 H 800. 6-benzothienyl 1 H 801. 6-benzofuryl 1 H 802.5-benzothienyl 1 H 803. 5-benzofuryl 1 H 804. 2-benzimidazolyl 1 H 805.2-benzoxazolyl 1 H 806. 2-benzthiazolyl 1 H 807. 6-benzimidazolyl 1 H808. 6-benzoxazolyl 1 H 809. 6-benzthiazolyl 1 H 810. 2-quinazolinyl 1 H811. 3-(phenoxy)-6-pyridyl 1 H 812. 4-(phenylcarbonyl)phenyl 1 H 813.4-(phenylamino)phenyl 1 H 814. 4-cyclohexyloxyphenyl 1 H 815.4-(3-thienyl)phenyl 1 H 816. 4-(pyrazol-3-yl)phenyl 1 H 817.3,4-dichlorophenyl 1 H

[1599] TABLE 9

# R¹ n R² 818. 4-chlorophenyl 1 6-F 819. 3-fluoro-4-methoxyphenyl 1 H820. 4-phenoxyphenyl 1 H 821. 4-biphenyl 1 H 822. 4-cyclohexylphenyl 1 H823. 2-quinolyl 1 H 824. 3-isoquinolyl 1 H 825. 3-quinolyl 1 H

EXAMPLE 826

[1600]

[1601] The titled compound was prepared from2,3-dihydrobenzo[b]furan-5-ylmethylamine by the method described inExample 25. MS: (ES+) 402 (M+1)⁺; (ES−): 400 (M−1)⁻. Calc'd. forC₂₅H₂₇N₃O₂: 401.21.

EXAMPLE 827

[1602]

[1603] The titled compound was prepared from2,3-dihydrobenzo[b]furan-5-ylmethylamine by the method described inExample 25. MS: (ES+) 414 (M+1)⁺; (ES−): 412 (M−1)⁻. Calc'd. forC₂₂H₁₈F₃N₃O₂: 413.14.

[1604] The following compounds (Examples 828-864) were synthesized bythe method described in Example 25 or Example 82 unless specificallydescribed. TABLE 10

# Y R¹ M + H calc'd 828. —NH(CH₂)₂—

375 374.2 829. —NH(CH₂)₂—

375 374.2 830. —NH(CH₂)₂—

411 410.2 831. —NH(CH₂)₂—

387 386.1 832. —NH(CH₂)₂—

361 360.2 833. —NH(CH₂)₂—

457 456.6 834. —NH(CH₂)₂—

437 436.4 835. —NH(CH₂)₂—

485.3 484.7 836. —NH(CH₂)₂—

388.3 387.5 837. —NH(CH₂)₂—

485.3 484.6 838. —NH(CH₂)₂—

486 485.5 839. —NH(CH₂)₂—

586.4 585.6 840. —NH(CH₂)₂—

564 563.6 841. —NH(CH₂)₂—

580 579.6 842. —NH(CH₂)₂—

564 563.6 843. —NH(CH₂)₂—

499.2 498.7 844. —NH(CH₂)₂—

512.1 511.6 845. —NH(CH₂)₂—

497.6 846. —NHCH₂—CH(4-morpholino)

521.5 847. —NH(CH₂)₂—

514 513.6 848. —NH(CH₂)₂—

548.6 849. —NH(CH₂)₂—

484.1 483.2 850. —NH(CH₂)₂—

438 437 851. —NH(CH₂)₂—

430.2 429.5 852. —NH(CH₂)₂—

429 428.6 853. —NH(CH₂)₂—

498.5 854. —NH(CH₂)₂—

599 598.6 855. —NH(CH₂)₂—

471.3 470.7 856. —NH(CH₂)₂—

458 457.3 857. —NH(CH₂)₂—

418.1 417.2 858. —NH(CH₂)₂—

402 401.1 859. —NH(CH₂)₂—

445.9 445.5 860. —NH(CH₂)₂—

432.1 431.5 861. —NH(CH₂)₂—

472.0 471.2 862. —NH(CH₂)₂—

416.3 415.2 863. —NH(CH₂)₂—

403.1 402.1 864. —NH(CH₂)₂—

472.1 471.2

EXAMPLE 865

[1605]

[1606] A solution of 2-fluoro-N-(4-trifluoromethyl-phenyl)-nicotinamide(107 mg) and[2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-yl]-methylamine (89 mg)and NaHCO₃ (95 mg) was dissolved in IpOH (10 ml) and heated to 80° C.for 18 h. After cooling to RT, the mixture was diluted with EtOAc (50ml) forming a precipitate which was filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (20% (12 N NH₃/MeOH)/EtOAc) to give the product as alight yellow oil. M+H 500.1; Calc'd 499.2.

[1607] The following compounds (Example 866-939) were synthesized by themethod described above.

[1608] 866)N-(4-tert-Butyl-phenyl)-2-{[2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 488.1; Calc'd—487.3

[1609] 867)2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide.M+H 485.3; Calc'd 484.6.

[1610] 868)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-nicotinamide.M+H 457.1; Calc'd 456.5.

[1611] 869)2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.M+H 612.6; Calc'd 611.8.

[1612] 870)2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-methylpiperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.M+H 526.3; Calc'd 525.7.

[1613] 871)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.M+H Calc'd 556.

[1614] 872)2-({2-[2-(1-Methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide.M+H Calc'd 513.

[1615] 873)N-(4-tert-Butyl-phenyl)-2-{[2-ethylpyridin-4-ylmethyl]-amino}-nicotinamide.

[1616] 874)N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.M+H Calc'd 487.

[1617] 875)2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H Calc'd 549.

[1618] 876)N-(4-Pentafluoroethyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H Calc'd 535.

[1619] 877)N-(4-tert-Butyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H Calc'd 473.

[1620] 878)N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 571.4; Calc'd 570.3.

[1621] 879)N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H Calc'd 584.

[1622] 880)N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl-ethylamino)-nicotinamide.M+H Calc'd 598.

[1623] 881)N-[3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H Calc'd 534.

[1624] 882)N-[3-(4-Boc-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 621.4; Calc'd 620.

[1625] 883)2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.

[1626] 884)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.

[1627] 885)2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 578.3. Calc'd 577.2.

[1628] 886)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.

[1629] 887)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 501.2; Calc'd 500.3.

[1630] 888)N-(1-Boc-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.

[1631] 889)N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 601.6; Calc'd 600.34.

[1632] 890)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1633] 891)N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.

[1634] 892)N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1635] 893)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

[1636] 894)N-[3,3-Dimethyl-1-(1-Boc-pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.

[1637] 895)N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.

[1638] 896)N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1639] 897)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 516.1.

[1640] 898)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 501.3.

[1641] 899)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.

[1642] 900)2-{[2-(3-Morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 566.

[1643] 901) (S)2-{[2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 536.

[1644] 902)N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 495. Calc'd 494.

[1645] 903)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 558; Calc'd 557.

[1646] 904)N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 504. Calc'd 503.

[1647] 905)N-(4-tert-Butyl-phenyl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 409; Calc'd 489.

[1648] 906)2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.M+H 502; Calc'd 501.

[1649] 907)2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.M+H 502; Calc'd 501.

[1650] 908)2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 552; Calc'd 551.

[1651] 909)N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 481; Calc'd 480.

[1652] 910)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 545; Calc'd 544.

[1653] 911)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.

[1654] 912)2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.

[1655] 913)2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.

[1656] 914)2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide.

[1657] 915) (R)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 474; Calc'd 473.

[1658] 916) (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1659] 917) (R)N-[3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 486; Calc'd 485.5.

[1660] 918)N-[3-(1-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1661] 919)N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.920)N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 560; Calc'd 559.

[1662] 921)N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.

[1663] 922)2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-trifluoromethyl-phenyl)-nicotinamide.

[1664] 923)2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide.

[1665] 924)2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-tert-butyl-phenyl)-nicotinamide.

[1666] 925)2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-tert-butyl-isoxazol-5-yl)-nicotinamide.

[1667] 926)N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.

[1668] 927)2-[(Pyridin-4-ylmethyl)-amino]-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide.

[1669] 928)N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

[1670] 929)N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 485.3; Calc'd 484.6.

[1671] The following compounds (Example 930-937) were synthesized by themethod described above, substituting K₂CO₃ for NaHCO₃.

[1672]930)2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 550.2; Calc'd 549.2.

[1673] 932)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 543.4; Calc'd 542.3.

[1674] 933)N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.M+H 504.3; Calc'd 503.6.

[1675] 934)2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 566.3; Calc'd 565.55.

[1676] 935)2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.M+H 516.0; Calc'd 515.5.

[1677] 936)N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H Calc'd 487.6.

[1678] 937)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H Calc'd 542.69.

[1679] The following compounds (Example 938-939) were synthesized by themethod described above, substituting Cs₂CO₃ for NaHCO₃.

[1680] 938)2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.M H 597.0; Calc'd 596.7.

[1681] 939)N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 479; Calc'd 478.3.

[1682] The following compounds (Example 940-945) were synthesized by themethod described above, substituting t-BuOH for IpOH.

[1683] 940)N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 558.1. Calc'd 557.6.

[1684] 941)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 588.1. Calc'd 587.2.

[1685] 942)2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide.M+H 404.5; Calc'd 403.2.

[1686] 943)N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 432.1; Calc'd 431.5.

[1687] 944)N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 404.5; Calc'd 403.2.

[1688] 945)2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide.M+H 598.4; Calc'd 597.3.

[1689] The following compounds (Example 946-993) were synthesized by themethod described above, unless specifically described.

[1690] 946)N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with MeOH as the solvent at 110° C. M+H 402.3.

[1691] 947)N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamidewas prepared with pentanol at 95° C. M+H Calc'd 501.

[1692] 948)N-(3-tert-Butyl-isoxazol-5-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamidewas prepared with pyridine at 95° C. M+H Calc'd 492.

[1693] 949)N-(3-trifluoromethylphenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamidewas prepared with pyridine at 95° C. M+H Calc'd 513.

[1694] 950)2-[(2,3-Dihydro-benzofuran-6-ylmethyl)-amino]-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamidewas prepared with DIEA at 120° C. M+H 663.4; Calc'd 662.6.

[1695] 951) (R)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 135° C. M+H 566.5; Calc'd565.5.

[1696] 952) (S)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 135° C. M+H 566.5; Calc'd565.5.

[1697] 953)N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 130° C. M+H 488.3; Calc'd487.6.

[1698] 954)N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 135° C. M+H 550.2; Calc'd549.5.

[1699] 955)N-[4-Pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 130° C. M+H 550.1; Calc'd549.5.

[1700] 956)N-[4-Trifluoromethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH as the solvent at 130° C. M+H 486.3; Calc'd485.5.

[1701] 957) (S)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with DIEA at 135° C. M+H 572. Calc'd 571.6.

[1702] 958) (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with DIEA at 130° C. M+H 622. Calc'd 621.6.

[1703] 959) (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with DIEA at 130° C. M+H 622.4. Calc'd 621.6.

[1704] 960)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamidewas prepared with pyridine and TEA at 90° C.M+H 474.

[1705] 961)N-(3-Trifluoromethyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamidewas prepared with pyridine and TEA at 90° C. M+H 486.

[1706] 962)N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamidewas prepared with pyridine and TEA at 90° C. M+H 465.

[1707] 963)N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with pyridine at 90° C. M+H 498; Calc'd 497.6.

[1708] 964)N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared at 130° C. neat. M+H 500. Calc'd 499.2.

[1709] 965)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamidewas prepared at 130° C. neat. M+H 602. Calc'd for C₃₀H₃₄F₃N₅O₅: 601.6.

[1710] 967)N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethoxy]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with DIEA and IpOH at 130° C. M+H 574.6.

[1711] 968)N-[4-tert-Butyl-3-(1-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH and DIEA at 130° C. M+H 546.

[1712] 969)N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared neat at 130° C. M+H 424; Calc'd 423.

[1713] 970)N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared neat at 130° C. M+H 415; Calc'd 414.

[1714] 971)N-{4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with pyridine. M+H 444; Calc'd 443.27.

[1715] 972)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamidewas prepared with pyridine and NaHCO₃ at 110° C. MS: 473 (M+H), Calc'dfor C₂₈H₃₅N₅O₂—472.6.

[1716] 973)N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with IpOH at 120° C. M+H 375. Calc'd for C₂₇H₃₂N₆O: 374.

[1717] 974)2-{[2-(3-Dimethylamino-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.M+H 524; Calc'd 523.2.

[1718] 975)N-[3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 470.4; Calc'd 469.21.

[1719] 976)2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.M+H 597.0; Calc'd 596.31.

[1720] 977)N-[3-(azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 458.1; Calc'd 457.2.

[1721] 978)N-(3-Hydroxy-5-trifluoromethyl-phenyl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 388.9; Calc'd 388.11.

[1722] 979)N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 430; Calc'd 429.22.

[1723] 980)N-[2-(4-methoxy-benzyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 522.3; Calc'd 521.24.

[1724] 981)N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(quinolin-4-ylmethyl)-amino]-benzamide.M+H 479; Calc'd 478.24.

[1725] 982)2-[(Pyridin-4-ylmethyl)-amino]-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide.M+H 486; Calc'd 485.

[1726] 983)2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.M+H 500.5; Calc'd 499.5.

[1727] 984)N-[3-(1-Boc-azetidin-3-ylmethoxy)-4-tert-butyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 546. Calc'd 545.

[1728] 985)2-Methyl-2-[4-({2-[(pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-phenyl]-propionicacid methyl ester. M+H 405; Calc'd 404.

[1729] 986)N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.M+H 504.3; Calc'd 503.

[1730] 987)N-(4-pentafluoroethyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.M+H 566.3; Calc'd 565.

[1731] 988)N-(4-trifluoromethyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.M+H 516.0; Calc'd 515.

[1732] 989)N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H 488.4; Calc'd 487.

[1733] 990)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H 543.5; Calc'd 542.

[1734] 991)N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-nicotinamide.M+H 459.3.

[1735] 992)2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-N-(3-trifluoromethylphenyl)-nicotinamide.M+H 500.4; Calc'd 499.

EXAMPLE 993

[1736]

[1737]N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide(300 mg, Example 871) was dissolved in conc. HCl (20 ml) and EtOH (20ML) and heated at 70° C. for 4 H. The mixture was concentrated and theresidue was diluted with sat'd NaHCO₃ and CH₂Cl₂. The organic layer wasdried over Na₂SO₄ and concentrated to obtain the desired compound. M+H515. Calc'd for C₃₀H₃₈N₆O₂: 514.

[1738] The following compounds (Example 995-1009) were synthesized bythe method described above, unless specifically described.

[1739] 995)N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 390.3; Calc'd 389.4.

[1740] 996)N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 388.3.

[1741] 997)N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 501.3; Calc'd 500.3.

[1742] 998)N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with 1N HCl in ether and dioxane at RT. M+H 457.2; Calc'd456.7.

[1743] 999)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H Calc'd 500.65.

[1744] 1000)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 404.3; Calc'd 403.2.

[1745] 1001)N-[3,3-Dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with HCl in EtOAc. M+H 501.4; Calc'd 500.3.

[1746] 1002)N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 487.4; Calc'd 486.3.

[1747] 1003)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamidewas prepared with HCl in EtOAc.

[1748] 1004)N-[3,3-Dimethyl-1-(pyrrolidin-2-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamidewas prepared with HCl in EtOAc.

[1749] 1005)2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamidewas prepared with HCl in EtOAc. M+H 501.3.

[1750] 1006)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 503; Calc'd 502.

[1751] 1007)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 529.

[1752] 1008)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide.M+H 516; Calc'd 515.

[1753] 1009)N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.M+H 501.4; Calc'd 500.

EXAMPLE 1010

[1754]

[1755] 2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TsOH(40 mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml)were stirred at 60 C. for 6 h. Treated with NaBH₄ (200 mg) and stirredfor 2 h at RT. MS (ES⁺) 566.3 (M+H)⁺; Calc'd for C₂₆H₂₈F₅N₇O₂—565.

EXAMPLE 1011

[1756]

[1757]2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide(210 mg) was heated at reflux with Et₃SiH (5 ml) and TFA (15 ml) for 9h. The mixture was concentrated, then diluted with CH₂Cl₂ (50 ml) andwashed with sat'd NaHCO₃ (50 ml) and brine (30 ml), dried over MgSO₄ andpurified by silica gel chromatography (10% MeOH/2M NH₃ 90% EtOAc) toafford the product as a yellow solid. M+H Calc'd for C₂₅H₂₉N₅O₂: 431.2.

EXAMPLE 1012

[1758]

[1759]N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide(110 mg) was dissolved in DMF and added NaH (30 mg). The mix was stirredfor 15 min then MeI (18 ul) was added and stirred for 10 min. TheSolvent was evaporated and purified by preparative TLC (10% MeOH/EtOAc)to give the product. M+H 438; Calc'd for C₂₂H₂₃N₅O₃S: 437.1.

[1760] The following compounds (Example 1013-1014) were synthesized bythe method described above, unless specifically described.

[1761] 1013)N-[3,3-Dimethyl-1,1-dioxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 535; Calc'd for C₂₈H₃₄N₆O₃S: 534.

[1762] 1014)N-[2-(2-Dimethylamino-ethyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.M+H 495; Calc'd 494.

EXAMPLE 1015

[1763]

[1764] M+H 529.4. Calc'd for 528.3.

EXAMPLE 1016

[1765]

[1766] M+H 429.2. Calc'd for 228.2.

EXAMPLE 1017

[1767]

[1768] M+H 663.4. Calc'd for 662.3.

EXAMPLE 1018

[1769]

[1770] M+H 381.3. Calc'd for.

EXAMPLE 1019

[1771]

[1772] M+H 430. Calc'd for.

EXAMPLE 1020

[1773]

[1774] M+H 432.2. Calc'd for.

[1775] Although the pharmacological properties of the compounds ofFormula I-XII vary with structural change, in general, activitypossessed by compounds of Formula I-XII may be demonstrated in vivo. Thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays. Theexemplified pharmacological assays which follow have been carried outwith the compounds according to the invention and their salts. Compoundsof the present invention showed inhibition of KDR kinase at doses lessthan 50 μM.

Biological Evaluation HUVEC Proliferation Assay

[1776] Human Umbilical Vein Endothelial cells are purchased fromClonetics, Inc., as cryopreserved cells harvested from a pool of donors.These cells, at passage 1, are thawed and expanded in EBM-2 completemedium, until passage 2 or 3. The cells are trypsinized, washed inDMEM+10% FBS+antibiotics, and spun at 1000 rpm for 10 min. Prior tocentrifugation of the cells, a small amount is collected for a cellcount. After centrifugation, the medium is discarded, and the cells areresuspended in the appropriate volume of DMEM+10% FBS+antibiotics toachieve a concentration of 3×10⁵ cells/mL. Another cell count isperformed to confirm the cell concentration. The cells are diluted to3×10⁴ cells/mL in DMEM+10% FBS+antibiotics, and 100 μL of cells areadded to a 96-well plate. The cells are incubated at 37° C. for 22 h.

[1777] Prior to the completion of the incubation period, compounddilutions are prepared. Five-point, five-fold serial dilutions areprepared in DMSO, at concentrations 400-fold greater than the finalconcentrations desired. 2.5 μL of each compound dilution are dilutedfurther in a total of 1 mL DMEM+10% FBS+antibiotics (400×dilution).Medium containing 0.25% DMSO is also prepared for the 0 μM compoundsample. At the 22-hour timepoint, the medium is removed from the cells,and 100 μL of each compound dilution is added. The cells are incubatedat 37° C. for 2-3 h.

[1778] During the compound pre-incubation period, the growth factors arediluted to the appropriate concentrations. Solutions of DMEM+10%FBS+antibiotics, containing either VEGF or bFGF at the followingconcentrations: 50, 10, 2, 0.4, 0.08, and 0 ng/mL are prepared. For thecompound-treated cells, solutions of VEGF at 550 ng/mL or bFGF at 220ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, areprepared since 10 μL of each will be added to the cells (110 μL finalvolume). At the appropriate time after adding the compounds, the growthfactors are added. VEGF is added to one set of plates, while bFGF isadded to another set of plates. For the growth factor control curves,the media on wells B4-G6 of plates 1 and 2 are replaced with mediacontaining VEGF or bFGF at the varying concentrations (50-0 ng/mL). Thecells are incubated at 37° C. for an additional 72 h.

[1779] At the completion of the 72 h incubation period, the medium isremoved, and the cells are washed twice with PBS. After the second washwith PBS, the plates are tapped gently to remove excess PBS, and thecells are placed at −70° C. for at least 30 min. The cells are thawedand analyzed using the CyQuant fluorescent dye (Molecular ProbesC-7026), following the manufacturer's recommendations. The plates areread on a Victor/Wallac 1420 workstation at 485 nm/530 nm(excitation/emission). Raw data are collected and analyzed using a4-parameter fit equation in XLFit. IC₅₀ values are then determined.

[1780] Examples 4, 7, 20-21, 25-26, 28, 33, 67, 72(f-i, n-o), 78, 82,84, 86, 94-95, 97-100, 105, 111-112, 115-118, 130, 133, 138, 140, 151,154-156, 158-159, 165, 167, 169, 817, 826-829, 831-838, 840-844, 845,847-851, 853, 855-860, 862, 864, 873, 900, 904-905, 916-917, 922-924,942-944, 946, 951-952, 954-955, 963-964, 973, 977-978, 982, 985, 991,995, 1000 and 1008 inhibited VEGF-stimulated HUVEC proliferation at alevel below 50 nm.

Angiogenesis Model

[1781] To determine the effects of the present compounds on angiogenesisin vivo, selective compounds are tested in the rat cornealneovascularization micropocket model or the angiogenesis assay ofPassaniti, Lab. Invest., 67, 519-28 (1992).

Rat Corneal Neovascularization Micropocket Model

[1782] In Life Aspects: Female Sprague Dawley rats weighingapproximately 250 g were randomized into one of five treatment groups.Pretreatment with the vehicle or compound was administered orally, 24 hprior to surgery and continued once a day for seven additional days. Onthe day of surgery, the rats were temporarily anesthetized in anIsofluorane gas chamber (delivering 2.5 liters/min oxygen+5%Isofluorane). An othoscope was then placed inside the mouth of theanimal to visualize the vocal cords. A tip-blunted wire was advanced inbetween the vocal cords and used as a guide for the placement of anendotracheal Teflon tube (Small Parts Inc. TFE-standard Wall R-SWTT-18).A volume-controlled ventilator (Harvard Apparatus, Inc. Model 683) wasconnected to the endotracheal tube to deliver a mixture of oxygen and 3%Isofluorane. Upon achieving deep anesthesia, the whiskers were cut shortand the eye areas and eyes gently washed with Betadine soap and rinsedwith sterile saline. The corneas were irrigated with one to two drops ofProparacaine HCl ophthalmic topical anesthetic solution (0.5%) (Bauschand Lomb Pharmaceuticals, Tampa Fla.). The rat was then positioned underthe dissecting microscope and the corneal surface brought into focus. Avertical incision was made on the midline of the cornea using a diamondblade knife. A pocket was created by using fine scissors to separate theconnective tissue layers of the stroma, tunneling towards the limbus ofthe eye. The distance between the apex of the pocket and the limbus wasapproximately 1.5 mm. After the pocket had been made, the soakednitrocellulose disk filter (Gelman Sciences, Ann Arbor Mich.) wasinserted under the lip of the pocket. This surgical procedure wasperformed on both eyes. rHu-bFGF soaked disks were placed into the righteye, and the rHu-VEGF soaked disks were placed into the left eye.Vehicle soaked disks were placed in both eyes. The disk was pushed intoposition at the desired distance from the limbal vessels. Ophthalmicantibiotic ointment was applied to the eye to prevent drying andinfection. After seven days, the rats were euthanized by CO₂asphyxiation, and the eyes enucleated. The retinal hemisphere of the eyewas windowed to facilitate fixation, and the eye placed into formalinovernight.

[1783] Post Mortem Aspects: After twenty-four hours in fixative, thecorneal region of interest was dissected out from the eye, using fineforceps and a razorblade. The retinal hemisphere was trimmed off and thelens extracted and discarded. The corneal dome was bisected and thesuperfluous cornea trimmed off. The iris, conjunctiva and associatedlimbal glands were then carefully teased away. Final cuts were made togenerate a square 3×3 mm containing the disk, the limbus, and the entirezone of neovascularization.

[1784] Gross Image Recording: The corneal specimens were digitallyphotographed using a Sony CatsEye DKC5000 camera (A.G. Heinz, IrvineCalif.) mounted on a Nikon SMZ-U stereo microscope (A. G. Heinz). Thecorneas were submerged in distilled water and photographed viatrans-illumination at approximately 5.0 diameters magnification.

[1785] Image analysis: Numerical endpoints were generated using digitalmicrographs collected from the whole mount corneas after trimming andwere used for image analysis on the Metamorph image analysis system(Universal Imaging Corporation, West Chester Pa.). Three measurementswere taken: Disk placement distance from the limbus, number of vesselsintersecting a 2.0 mm perpendicular line at the midpoint of the diskplacement distance, and percent blood vessel area of the diffusiondetermined by thresholding.

[1786] General Formulations:

[1787] 0.1% BSA in PBS vehicle: 0.025 g of BSA was added to 25.0 ml ofsterile 1× phosphate buffered saline, gently shaken until fullydissolved, and filtered at 0.2 μm. Individual 1.0 ml samples werealiquoted into 25 single use vials, and stored at −20° C. until use. Forthe rHu-bFGF disks, a vial of this 0.1% BSA solution was allowed to thawat room temperature. Once thawed, 10 μl of a 100 mM stock solution ofDTT was added to the 1 ml BSA vial to yield a final concentration of 1mM DTT in 0.1% BSA.

[1788] rHu-VEGF Dilutions:

[1789] Prior to the disk implant surgery, 23.8 μl of the 0.1% BSAvehicle above was added to a 10 μg rHu-VEGF lyophilized vial yielding afinal concentration of 10 μM. rHu-bFGF: Stock concentration of 180ng/μl: R&D rHu- bFGF: Added 139 μl of the appropriate vehicle above tothe 25 μg vial lyophilized vial. 13.3 μl of the [180 ng/μl] stock vialand added 26.6 μl of vehicle to yield a final concentration of 3.75 μMconcentration.

[1790] Nitro-cellulose disk preparation: The tip of a 20-gauge needlewas cut off square and beveled with emery paper to create a punch. Thistip was then used to cut out ≡0.5 mm diameter disks from anitrocellulose filter paper sheet (Gelman Sciences). Prepared disks werethen placed into Eppendorf microfuge tubes containing solutions ofeither 0.1% BSA in PBS vehicle, 10 μM rHu-VEGF (R&D Systems,Minneapolis, Minn.), or 3.75 μM rHu-bFGF (R&D Systems, Minneapolis,Minn.) and allowed to soak for 45-60 min before use. Each nitrocellulosefilter disk absorbs approximately 0.1 μl of solution.

[1791] In the rat micropocket assay, compounds of the present inventionwill inhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

[1792] A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs) (n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.Compounds of the present invention are active at doses less than 150mpk.

Rat Adjuvant Arthritis Model

[1793] The rat adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol.91, 95-101 (1956)) is used to test the anti-arthritic activity ofcompounds of the formula I, or salts thereof. Adjuvant Arthritis can betreated using two different dosing schedules: either (i) starting timeof immunization with adjuvant (prophylactic dosing); or from day 15 whenthe arthritic response is already established (therapeutic dosing).Preferably a therapeutic dosing schedule is used.

Rat Carrageenan-induced Analgesia Test

[1794] The rat carrageenan analgesia test was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined.

[1795] Formulations

[1796] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Thecompounds and compositions of the present invention may, for example, beadministered orally, mucosally, topically, rectally, pulmonarily such asby inhalation spray, or parentally including intravascularly,intravenously, intraperitoneally, subcutaneously, intramuscularlyintrasternally and infusion techniques, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles.

[1797] The pharmaceutically active compounds of this invention can beprocessed in accordance with conventional methods of pharmacy to producemedicinal agents for administration to patients, including humans andother mammals.

[1798] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg or 5 to 1000 mg. A suitable daily dosefor a human or other mammal may vary widely depending on the conditionof the patient and other factors, but, once again, can be determinedusing routine methods.

[1799] The amount of compounds which are administered and the dosageregimen for treating a disease condition with the compounds and/orcompositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, thetype of disease, the severity of the disease, the route and frequency ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. A daily dose of about 0.01 to 500 mg/kg, preferably betweenabout 0.1 and about 50 mg/kg, and more preferably about 0.1 and about 20mg/kg body weight may be appropriate. The daily dose can be administeredin one to four doses per day.

[1800] For therapeutic purposes, the active compounds of this inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

[1801] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[1802] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

[1803] When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs.

[1804] The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[1805] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

[1806] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[1807] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The active ingredients are preferably present insuch formulations in a concentration of 0.5 to 20%, advantageously 0.5to 10% and particularly about 1.5% w/w.

[1808] Formulations for parenteral administration may be in the form ofaqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules using one or more of the carriers ordiluents mentioned for use in the formulations for oral administrationor by using other suitable dispersing or wetting agents and suspendingagents. The compounds may be dissolved in water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride, tragacanth gum, and/or variousbuffers. Other adjuvants and modes of administration are well and widelyknown in the pharmaceutical art. The active ingredient may also beadministered by injection as a composition with suitable carriersincluding saline, dextrose, or water, or with cyclodextrin (ie.Captisol), cosolvent solubilization (ie. propylene glycol) or micellarsolubilization (ie. Tween 80).

[1809] The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[1810] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[1811] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable non-irritating excipientsuch as cocoa butter and polyethylene glycols that are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[1812] The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[1813] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[1814] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

[1815] All mentioned references, patents, applications and publications,are hereby incorporated by reference in their entirety, as if herewritten.

What is claimed is:
 1. A compound of formula I

wherein each of A¹ and A² is independently C, or N; wherein ring A isselected from a) 5- or 6-membered partially saturated heterocyclyl, b)5- or 6-membered heteroaryl, c) 9- or 10-membered fused partiallysaturated heterocyclyl, d) 9-, 10- or 11-membered fused heteroaryl; e)naphthyl, and f) 4-, 5- or 6- membered cycloalkenyl; wherein X isselected from

wherein Z is oxygen or sulfur; wherein Y is selected from

wherein p is 0 to 2, wherein R^(a) and R^(b) are independently selectedfrom H, halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₆ cycloalkyl; wherein R^(z) isselected from C₁-C₄ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—; wherein R^(d) is cycloalkyl;wherein R is selected from a) substituted or unsubstituted 5-6 memberedheterocyclyl, and b) substituted or unsubstituted fused 9-, 10- or11-membered heterocyclyl; wherein substituted R is substituted with oneor more substituents independently selected from halo, —OR³, —SR³,—SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, lower alkyl substitutedwith R², cyano, nitro, lower alkenyl and lower alkynyl; wherein R¹ isselected from a) substituted or unsubstituted 6-10 membered aryl, b)substituted or unsubstituted 5-6 membered heterocyclyl, c) substitutedor unsubstituted 9-11 membered fused heterocyclyl, d) cycloalkyl, and e)cycloalkenyl, wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl; wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl; wherein R³ is independentlyselected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆cycloalkyl, and lower haloalkyl; wherein R⁴ is independently selectedfrom C₂-C₄ alkylenyl, C₂-C₄ alkenylenyl and C₂-C₄ alkynylenyl, where oneof the CH₂ groups may be substituted with an oxygen atom or an —NH—;wherein R⁵ is selected from H, lower alkyl, phenyl and lower aralkyl;and wherein R⁶ is selected from H or C₁₋₆-alkyl; wherein R¹⁴ is selectedfrom H, phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl; andpharmaceutically acceptable salts thereof; provided A is not naphthylwhen X is —C(O)NH— and when R¹ is phenyl when Y is —NHCH₂— and when R is4-pyridyl; further provided A is not pyridyl when X is —C(O)NH— and whenY is —NHCH₂— and when R is 4-pyridylpiperidin-4-yl,1-tertbutylpiperidin-4-yl, 1-isopropylpiperidin-4-yl or1-cycloalkylpiperidin-4-yl; further provided A is not pyridyl when X is—C(O)NH— and when R¹ is4-[3-(3-pyridyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is—NHCH₂— and when R is 4-pyridyl; and further provided R is notunsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH₂—. 2.Compound of claim 1, and pharmaceutically acceptable salts thereof,wherein A is selected from 5- or 6- membered partially saturatedheterocyclyl.
 3. Compound of claim 2, and pharmaceutically acceptablesalts thereof, wherein A is selected from dihydropyran, dihydrothienyl,dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl,dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyland pyrazolinyl; wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, cyano,and C₁₋₂-alkyl substituted with R², or wherein R^(a) and R^(b) togetherform C₃-C₄ cycloalkyl; wherein R^(z) is C₁-C₂ alkylenyl, where one ofthe CH₂ groups may be substituted with an oxygen atom or an —NH—;wherein R is selected from substituted or unsubstituted 5-6 memberedheteroaryl comprising one or more nitrogen atoms, and substituted orunsubstituted 9-10 membered fused heteroaryl comprising one or morenitrogen atoms; wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl;wherein R¹ is selected from substituted or unsubstituted aryl selectedfrom phenyl, naphthyl, indenyl and tetrahydronaphthyl, substituted orunsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted9-10 membered fused heteroaryl; wherein substituted R¹ is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³),—(C₁-C₂ alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,nitro and C₁₋₂-haloalkyl; wherein R² is one or more substituentsindependently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³,—COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro,C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl; wherein R³ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl; whereinR⁴ is C₂₋₃-alkylenyl, where one of the CH₂ groups may be substitutedwith an oxygen atom or an —NH—; and wherein R⁵ is selected from H andC₁₋₂-alkyl.
 4. Compound of claim 1, and pharmaceutically acceptablesalts thereof, wherein A is selected from 5- or 6-membered heteroaryl.5. Compound of claim 4, and pharmaceutically acceptable salts thereof,wherein A is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,pyrazolyl, isoxazolyl, triazolyl and isothiazolyl; wherein X is selectedfrom

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, cyano,and C₁₋₂-alkyl substituted with R², or wherein R^(a) and R^(b) togetherform C₃-C₄ cycloalkyl; wherein R^(z) is C₁-C₂ alkylenyl, where one ofthe CH₂ groups may be substituted with an oxygen atom or an —NH—;wherein R is selected from substituted or unsubstituted 5-6 memberedheteroaryl comprising one or more nitrogen atoms, and substituted orunsubstituted 9-10 membered fused heteroaryl comprising one or morenitrogen atoms; wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl;wherein R¹ is selected from substituted or unsubstituted aryl selectedfrom phenyl, naphthyl, indenyl and tetrahydronaphthyl, substituted orunsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted9-10 membered fused heteroaryl; wherein substituted R¹ is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³),—(C₁-C₂ alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,nitro and C₁₋₂-haloalkyl; wherein R² is one or more substituentsindependently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³,—COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro,C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl; wherein R³ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl; whereinR⁴ is C₂₋₃-alkylenyl, where one of the CH₂ groups may be substitutedwith an oxygen atom or an —NH—; and wherein R⁵ is selected from H andC₁₋₂-alkyl.
 6. Compound of claim 1 wherein A is selected from

wherein R^(c) is selected from H, methyl and optionally substitutedphenyl; wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, cyano,and C₁₋₂-alkyl substituted with R², or wherein R^(a) and R^(b) togetherform C₃-C₄ wherein R^(z) is C₁-C₂ alkylenyl, where one of the CH₂ groupsmay be substituted with an oxygen atom or an —NH—; wherein R is selectedfrom substituted or unsubstituted 5-6 membered heteroaryl comprising oneor more nitrogen atoms, and substituted or unsubstituted 9-10 memberedfused heteroaryl comprising one or more nitrogen atoms; whereinsubstituted R is substituted with one or more substituents independentlyselected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ isselected from substituted or unsubstituted aryl selected from phenyl,naphthyl, indenyl and tetrahydronaphthyl, substituted or unsubstituted5-6 membered heteroaryl, and substituted or unsubstituted 9-10 memberedfused heteroaryl; wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —SO₂R³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³), —(C₁-C₂alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,nitro and C₁₋₂-haloalkyl; wherein R² is one or more substituentsindependently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³,—COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro,C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl; wherein R³ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl; whereinR⁴ is C₂₋₃-alkylenyl, where one of the CH₂ groups may be substitutedwith an oxygen atom or an —NH—; and wherein R⁵ is selected from H andC₁₋₂-alkyl.
 7. Compound of claim 6 wherein A is selected from

wherein R^(c) is selected from H, methyl and optionally substitutedphenyl; wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, andC₁₋₂-alkyl; wherein R^(z) is C₁-C₂ alkylenyl; wherein R is selected fromsubstituted or unsubstituted 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 4-pyridazinyl, 6-pyridazinyl, indazolyl, quinolinyl,isoquinolinyl, quinazolinyl, triazolyl and 4-pyrazolyl; whereinsubstituted R is substituted with one or more substituents independentlyselected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ is asubstituted or unsubstituted substituent selected from phenyl, indenyl,thienyl, indolyl, pyridyl, naphthyl, tetrahydronaphthyl,2,1,3-benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrahydroquinolinyl, benzodioxanyl, quinazolinyl, furyl and pyrrolyl;wherein substituted R¹ is substituted with one or more substituentsindependently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³,—NR³R³, —NH(C₁-C₂-alkylenyl-R³), —(C₁-C₂-alkylenyl)NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted phenyl-C₁₋₂-alkylenyl, optionally substituted 5-6membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R² is one or moresubstituents independently selected from H, halo, —OR³, oxo, —SR³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;wherein R³ is selected from H, methyl, ethyl, cyclopropyl, cyclohexyland trifluoromethyl; wherein R⁴ is C₂₋₃-alkylenyl; and wherein R⁵ isfrom H, methyl or ethyl; and pharmaceutically acceptable salts thereof.8. Compound of claim 6 wherein A is selected from

wherein R^(c) is selected from H, methyl and optionally substitutedphenyl; wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, andC₁₋₂-alkyl; wherein R^(z) is C₁-C₂ alkylenyl; wherein R is selected fromsubstituted or unsubstituted 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 4-pyridazinyl, 6-pyridazinyl, indazolyl, quinolinyl,isoquinolinyl, quinazolinyl, triazolyl and 4-pyrazolyl; whereinsubstituted R is substituted with one or more substituents independentlyselected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ is asubstituted or unsubstituted substituent selected from phenyl, indenyl,thienyl, indolyl, pyridyl, naphthyl, tetrahydronaphthyl,2,1,3-benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrahydroquinolinyl, benzodioxanyl, quinazolinyl, furyl and pyrrolyl;wherein substituted R¹ is substituted with one or more substituentsindependently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³,—NR³R³, —NH(C₁-C₂-alkylenyl-R³), —(C₁-C₂-alkylenyl)NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted phenyl-C₁₋₂-alkylenyl, optionally substituted 5-6membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R² is one or moresubstituents independently selected from H, halo, —OR³, oxo, —SR³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;wherein R³ is selected from H, methyl, ethyl, cyclopropyl, cyclohexyland trifluoromethyl; wherein R⁴ is C₂₋₃-alkylenyl; and wherein R⁵ isfrom H, methyl or ethyl; and pharmaceutically acceptable salts thereof.9. Compound of claim 6 wherein A is selected from

wherein R^(c) is selected from H, methyl and optionally substitutedphenyl; wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, andC₁₋₂-alkyl; wherein R^(z) is C₁-C₂ alkylenyl; wherein R is selected fromsubstituted or unsubstituted 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 4-pyridazinyl, 6-pyridazinyl, indazolyl, quinolinyl,isoquinolinyl, quinazolinyl, triazolyl and 4-pyrazolyl; whereinsubstituted R is substituted with one or more substituents independentlyselected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁ ₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ is asubstituted or unsubstituted substituent selected from phenyl, indenyl,thienyl, indolyl, pyridyl, naphthyl, tetrahydronaphthyl,2,1,3-benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrahydroquinolinyl, benzodioxanyl, quinazolinyl, furyl and pyrrolyl;wherein substituted R¹ is substituted with one or more substituentsindependently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³,—NR³R³, —NH (C₁-C₂-alkylenyl-R³), —(C₁-C₂-alkylenyl)NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted phenyl-C₁₋₂-alkylenyl, optionally substituted 5-6membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R² is one or moresubstituents independently selected from H, halo, —OR³, oxo, —SR³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;wherein R³ is selected from H, methyl, ethyl, cyclopropyl, cyclohexyland trifluoromethyl; wherein R⁴ is C₂₋₃-alkylenyl; and wherein R⁵ isfrom H, methyl or ethyl; and pharmaceutically acceptable salts thereof.10. Compound of claim 1, and pharmaceutically acceptable salts thereof,wherein A is selected from

wherein X is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, andC₁₋₂-alkyl; wherein R^(z) is C₁-C₂ alkylenyl; wherein R is selected fromsubstituted or unsubstituted 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 4-pyridazinyl, 6-pyridazinyl, indazolyl, quinolinyl,isoquinolinyl, quinazolinyl, triazolyl and 4-pyrazolyl; whereinsubstituted R is substituted with one or more substituents independentlyselected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl,cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ is asubstituted or unsubstituted substituent group selected from phenyl,indenyl, thienyl, indolyl, pyridyl, naphthyl, tetrahydronaphthyl,2,1,3-benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrahydroquinolinyl, benzodioxanyl, quinazolinyl, furyl and pyrrolyl;wherein substituted R¹ is substituted with one or more substituentsindependently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³,—NR³R³, —NH(C₁-C₂-alkylenyl-R³), —(C₁-C₂-alkylenyl)NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,optionally substituted phenyl-C₁₋₂-alkylenyl, optionally substituted 5-6membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R² is one or moresubstituents independently selected from H, halo, —OR³, oxo, —SR³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;wherein R³ is selected from H, methyl, ethyl, cyclopropyl, cyclohexyland trifluoromethyl; wherein R⁴ is C₂₋₃-alkylenyl; and wherein R⁵ isfrom H, methyl or ethyl; and pharmaceutically acceptable salts thereof.11. Compound of claim 10, and pharmaceutically acceptable salts thereof,wherein A is

or

wherein X is —C(O)—NH—; wherein Y is —NH—CH₂—; wherein R is selectedfrom substituted or unsubstituted 4-pyridyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 5-indazolyl,4-pyrimidinyl and 4-pyridazinyl; wherein substituted R is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R¹ is selected fromsubstituted or unsubstituted phenyl, indazolyl, indolyl,2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl,benzodioxanyl, and quinazolinyl; wherein substituted R¹ is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁₋₂-alkylenyl, morpholinylmethyl,methylpiperdinylmethyl, methylpiperazinylmethyl, C₁₋₂-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R² is one or moresubstituents independently selected from H, halo, —OR³, oxo, —SR³,—CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)(OR³, —NR³C(O)R³,cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,C₁₋₃-carboxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;wherein R³ is selected from H, methyl, ethyl, cyclopropyl, cyclohexyland trifluoromethyl; wherein R⁴ is C₂₋₃-alkylenyl; and wherein R⁵ isfrom H, methyl or ethyl.
 12. Compound of claim 1 wherein A is 9- or10-membered fused partially saturated heterocyclyl or 9- or 10-memberedfused heteroaryl; wherein x is selected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, cyano,and C₁₋₂-alkyl substituted with R², or wherein R^(a) and R^(b) togetherform C₃-C₄ cycloalkyl; wherein R^(z) is C₁-C₂ alkylenyl, where one ofthe CH₂ groups may be substituted with an oxygen atom or an —NH—;wherein R is selected from substituted or unsubstituted 5-6 memberedheteroaryl comprising one or more nitrogen atoms, and substituted orunsubstituted 9-10 membered fused heteroaryl comprising one or morenitrogen atoms; wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl;wherein R¹ is selected from substituted or unsubstituted aryl selectedfrom phenyl, naphthyl, indenyl and tetrahydronaphthyl, substituted orunsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted9-10 membered fused heteroaryl; wherein substituted R¹ is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³),—(C₁-C₂ alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,nitro and C₁₋₂-haloalkyl; wherein R² is one or more substituentsindependently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³,—COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro,C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl; wherein R³ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl; whereinR⁴ is C₂₋₃-alkylenyl, where one of the CH₂ groups may be substitutedwith an oxygen atom or an —NH—; and wherein R⁵ is selected from H andC₁₋₂-alkyl; and pharmaceutically acceptable salts thereof.
 13. Compoundof claim 12 wherein A is selected from benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, indolyl,isoindolyl, quinolyl, isoquinolyl, naphthpyridinyl, tetrahydroquinolyl,quinoxalinyl and quinazolinyl; and pharmaceutically acceptable saltsthereof.
 14. Compound of claim 1, and pharmaceutically acceptable saltsthereof, wherein A is 5- or 6-membered cycloalkenyl; wherein X isselected from

wherein Y is selected from

wherein R^(a) and R^(b) are independently selected from H, halo, cyano,and C₁₋₂-alkyl substituted with R², or wherein R^(a) and R^(b) togetherform C₃-C₄ cycloalkyl; wherein R^(z) is C₁-C₂ alkylenyl, where one ofthe CH₂ groups may be substituted with an oxygen atom or an —NH—;wherein R is selected from substituted or unsubstituted 5-6 memberedheteroaryl comprising one or more nitrogen atoms, and substituted orunsubstituted 9-10 membered fused heteroaryl comprising one or morenitrogen atoms; wherein substituted R is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl;wherein R¹ is selected from substituted or unsubstituted aryl selectedfrom phenyl, naphthyl, indenyl and tetrahydronaphthyl, substituted orunsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted9-10 membered fused heteroaryl; wherein substituted R¹ is substitutedwith one or more substituents independently selected from halo, —OR³,—SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂ alkylenylR³),—(C₁-C₂ alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl,nitro and C₁₋₂-haloalkyl; wherein R² is one or more substituentsindependently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³,—COR³, —NR³ R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl, nitro,C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl; wherein R³ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl and C₁₋₂-haloalkyl; whereinR⁴ is C₂₋₃-alkylenyl, where one of the CH₂ groups may be substitutedwith an oxygen atom or an —NH—; and wherein R⁵ is selected from H andC₁₋₂-alkyl.
 15. Compound of claim 14 wherein A is cyclopentadienyl orcyclopentenyl; and pharmaceutically acceptable salts thereof. 16.Compound of claim 1 and pharmaceutically acceptable salts thereofselected fromN-(4-chlorophenyl)-3-[(4-pyridinylmethylene)amino]-4-pyridinecarboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;N-phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;N-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;N-(3-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide;N-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;{6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide;N-(3-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide;N-(3-fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(5-quinolylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide;N-(4-chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide;andN-(4-chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide.17. A compound of claim 1 having Formula II

wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂; wherein n is 1-2; wherein R is selected from a)unsubstituted or substituted 5- or 6-membered nitrogen-containingheteroaryl, and b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl, where R is substituted with one or moresubstituents selected from halo, amino, hydroxy, C₁₋₆-alkyl,C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹ is selected fromunsubstituted or substituted aryl, 5-6 membered heteroaryl and 9-10membered fused heteroaryl, wherein substituted R¹ is substituted withone or more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl,C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl, optionallysubstituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy,C₁₋₆-haloalkyl, and C₁₋₆-alkoxy; wherein R² is one or more substituentsindependently selected from H, halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₁₋₆-carboxyalkyl, unsubstituted orsubstituted aryl and unsubstituted or substituted 5-6 memberedheteroaryl; and wherein R⁶ is H or C₁₋₆-alkyl; and pharmaceuticallyacceptable isomers and salts thereof.
 18. Compound of claim 17 whereinR^(a) and R^(b) are H; wherein n is 1-2; wherein R is selected from4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl,indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl, whereR is unsubstituted or substituted with one or more substituents selectedfrom chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy and ethoxy; wherein R¹ is selected from phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl, where R¹ isunsubstituted or substituted with one or more substituents selected fromchloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; andwherein R² is one or more substituents independently selected from H,chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and pharmaceutically acceptable salts thereof.
 19. A compoundof claim 1 having Formula III

wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂; wherein n is 1-2; wherein R is selected from a)unsubstituted or substituted 5- or 6-membered nitrogen-containingheteroaryl, and b) unsubstituted or substituted 9- or 10-membered fusednitrogen-containing heteroaryl, where R is substituted with one or moresubstituents selected from halo, amino, hydroxy, C₁₋₆-alkyl,C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹ is selected fromunsubstituted or substituted aryl, 5-6 membered heteroaryl and 9-10membered fused heteroaryl, wherein substituted R¹ is substituted withone or more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₆-haloalkoxy,optionally substituted phenyloxy, benzyl, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, andC₁₋₆-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₁₋₆-carboxyalkyl, unsubstituted or substituted aryland unsubstituted or substituted 5-6 membered heteroaryl; and wherein R⁶is H or C₁₋₆-alkyl; and pharmaceutically acceptable isomers and saltsthereof.
 20. Compound of claim 19 wherein R^(a) and R^(b) are H; whereinn is 1-2; wherein R is selected from 4-pyridyl, pyrimidinyl,pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,naphthyridinyl and quinozalinyl, where R is unsubstituted or substitutedwith one or more substituents selected from chloro, fluoro, amino,hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;wherein R¹ is selected from phenyl, tetrahydronaphthyl, naphthyl,isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl,isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl,indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 21. A compound of claim 1 having Formula IV

wherein A³ is selected from CR² and N; wherein A⁴ is selected from CR²and N; provided one of A³ and A⁴ is not CR²; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶⁾ ₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, C₁₋₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy; wherein R²is one or more substituents independently selected from H, halo,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.22. Compound of claim 21 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 23. A compound of claim 1 having the formula V

wherein A⁵ is selected from S, O and NR⁶; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶)₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.24. Compound of claim 23 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 25. A compound of claim 1 having the formula

wherein A⁵ is selected from S, O and NR⁶; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶)₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.26. Compound of claim 25 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 27. A compound of claim 1 having the formula

wherein A⁵ is selected from S, O and NR⁶; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶)₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.28. Compound of claim 27 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 29. Compound of claim 1 of the formulas

wherein A⁵ is selected from S, O and NR⁶; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶)₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.30. Compound of claim 29 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 31. Compound of claim 1 of the formula

wherein A⁵ is selected from S, O and NR⁶; wherein R^(a) and R^(b) areindependently selected from H, halo, C₁₋₄-alkyl and —N(R⁶)₂; wherein nis 1-2; wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; and pharmaceutically acceptable isomers and salts thereof.32. Compound of claim 31 wherein R^(a) and R^(b) are H; wherein n is1-2; wherein R is selected from 4-pyridyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyland quinozalinyl, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R¹ isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, cyclohexyl,phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy,methoxy and ethoxy; and wherein R² is one or more substituentsindependently selected from H, chloro, fluoro, bromo, amino, hydroxy,methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl andunsubstituted or substituted heteroaryl selected from thienyl, furanyl,pyridyl, imidazolyl, and pyrazolyl; and pharmaceutically acceptablesalts thereof.
 33. Compound of claim 1 of the formula

wherein A⁵ is selected from S, O and NR⁶; wherein A⁶ is selected fromCR² and N; wherein R is selected from a) unsubstituted or substituted 5-or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused nitrogen-containing heteroaryl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and C₁₋₆-alkoxy; wherein R¹is selected from unsubstituted or substituted aryl, 5-6 memberedheteroaryl and 9-10 membered fused heteroaryl, wherein substituted R¹ issubstituted with one or more substituents selected from halo,C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl, optionallysubstituted phenyl, C₁₋₆-haloalkoxy, optionally substituted phenyloxy,benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;wherein R² is one or more substituents independently selected from H,halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, unsubstituted or substituted aryl and unsubstitutedor substituted 5-6 membered heteroaryl; and wherein R⁶ is H orC₁₋₆-alkyl; wherein

wherein R^(a) and R^(b) are independently selected from H, halo,C₁₋₄-alkyl and —N(R⁶)₂; and wherein n is 1-2; and pharmaceuticallyacceptable isomers and salts thereof.
 34. Compound of claim 33 whereinR^(a) and R^(b) are H; wherein n is 1-2; wherein R is selected from4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl,quinolyl, isoquinolyl, naphthyridinyl and quinozalinyl, where R isunsubstituted or substituted with one or more substituents selected fromchloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl,methoxy and ethoxy; wherein R¹ is selected from phenyl,tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, or benzthiazolyl, where R¹ isunsubstituted or substituted with one or more substituents selected fromchloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; andwherein R² is one or more substituents independently selected from H,chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; and pharmaceutically acceptable salts thereof.
 35. Apharmaceutical composition comprising a pharmaceutically-acceptablecarrier and a compound as in any of claims 1-34.
 36. A method oftreating cancer in a subject, said method comprising administering aneffective amount of a compound of formula I

wherein each of A¹ and A² is independently C or N; wherein ring A isselected from a) 5- or 6-membered partially saturated heterocyclyl, b)5- or 6-membered heteroaryl, c) 9- or 10-membered fused partiallysaturated heterocyclyl, d) 9-, 10- or 11-membered fused heteroaryl; e)naphthyl, and f) 4-, 5- or 6- membered cycloalkenyl; wherein X isselected from

wherein Z is oxygen or sulfur; wherein Y is selected from

wherein p is 0 to 2, wherein R^(a) and R^(b) are independently selectedfrom H, halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₆ cycloalkyl; wherein R^(z) isselected from C₁-C₄ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—; wherein R^(d) is cycloalkyl;wherein R is selected from a) substituted or unsubstituted 5-6 memberedheterocyclyl, and b) substituted or unsubstituted fused 9-, 10- or11-membered heterocyclyl; wherein substituted R is substituted with oneor more substituents independently selected from halo, —OR³, —SR³,—SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, lower alkyl substitutedwith R², cyano, nitro, lower alkenyl and lower alkynyl; wherein R¹ isselected from a) substituted or unsubstituted 6-10 membered aryl, b)substituted or unsubstituted 5-6 membered heterocyclyl, c) substitutedor unsubstituted 9-11 membered fused heterocyclyl, d) cycloalkyl, and e)cycloalkenyl,  wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH (C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl; wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl; wherein R³ is selected from H,lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, andlower haloalkyl; wherein R⁴ is independently selected from C₂-C₄alkylenyl, C₂-C₄ alkenylenyl and C₂-C₄ alkynylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—; wherein R⁵ isselected from H, lower alkyl, phenyl and lower aralkyl; and wherein R⁶is selected from H or C₁₋₆-alkyl; wherein R¹⁴ is selected from H,phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl;  andpharmaceutically acceptable salts thereof; provided A is not naphthylwhen X is —C(O)NH— and when R¹ is phenyl when Y is —NCH₂— and when R is4-pyridyl; and further provided R is not unsubstituted 2-thienyl,2-pyridyl or 3-pyridyl when Y is —NHCH₂—.
 37. The method of claim 36comprising a combination with a compound selected from antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents and miscellaneous agents.38. A method of treating angiogenesis in a subject, said methodcomprising administering an effective amount of a compound as in any ofFormula I

wherein each of A¹ and A² is independently C or N; wherein ring A isselected from a) 5- or 6-membered partially saturated heterocyclyl, b)5- or 6-membered heteroaryl, c) 9- or 10-membered fused partiallysaturated heterocyclyl, d) 9-, 10- or 11-membered fused heteroaryl; e)naphthyl, and f) 4-, 5- or 6- membered cycloalkenyl; wherein X isselected from

wherein Z is oxygen or sulfur; wherein Y is selected from

wherein p is 0 to 2, wherein R^(a) and R^(b) are independently selectedfrom H, halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₆ cycloalkyl; wherein R^(z) isselected from C₁-C₄ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—; wherein R^(d) is cycloalkyl;wherein R is selected from a) substituted or unsubstituted 5-6 memberedheterocyclyl, and b) substituted or unsubstituted fused 9-, 10- or11-membered heterocyclyl; wherein substituted R is substituted with oneor more substituents independently selected from halo, —OR, —SR³,—SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, lower alkyl substitutedwith R², cyano, nitro, lower alkenyl and lower alkynyl; wherein R¹ isselected from a) substituted or unsubstituted 6-10 membered aryl, b)substituted or unsubstituted 5-6 membered heterocyclyl, c) substitutedor unsubstituted 9-11 membered fused heterocyclyl, d) cycloalkyl, and e)cycloalkenyl, wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl; wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl; wherein R³ is selected from H,lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, andlower haloalkyl; wherein R⁴ is independently selected from C₂-C₄alkylenyl, C₂-C₄ alkenylenyl and C₂-C₄ alkynylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—; wherein R⁵ isselected from H, lower alkyl, phenyl and lower aralkyl; and wherein R⁶is selected from H or C₁₋₆-alkyl; wherein R¹⁴ is selected from H,phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl;  andpharmaceutically acceptable salts thereof; provided A is not naphthylwhen X is —C(O)NH— and when R¹ is phenyl when Y is —NCH₂— and when R is4-pyridyl; and further provided R is not unsubstituted 2-thienyl,2-pyridyl or 3-pyridyl when Y is —NHCH₂—.
 39. A compound as in any ofclaims 1-34 for use in a method of therapeutic treatment for the humanor animal body.
 40. A method of treating KDR-related disorders in amammal, said method comprising administering an effective amount of acompound of Formula I

wherein each of A¹ and A² is independently C or N; wherein ring A isselected from a) 5- or 6-membered partially saturated heterocyclyl, b)5- or 6-membered heteroaryl, c) 9- or 10-membered fused partiallysaturated heterocyclyl, d) 9-, 10- or 11-membered fused heteroaryl; e)naphthyl, and f) 4-, 5- or 6- membered cycloalkenyl; wherein X isselected from

wherein Z is oxygen or sulfur; wherein Y is selected from

wherein p is 0 to 2, wherein R^(a) and R^(b) are independently selectedfrom H, halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₆ cycloalkyl; wherein R^(z) isselected from C₁-C₄ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—; wherein R^(d) is cycloalkyl;wherein R is selected from a) substituted or unsubstituted 5-6 memberedheterocyclyl, and b) substituted or unsubstituted fused 9-, 10- or11-membered heterocyclyl; wherein substituted R is substituted with oneor more substituents independently selected from halo, —OR³, —SR³,—SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, lower alkyl substitutedwith R², cyano, nitro, lower alkenyl and lower alkynyl; wherein R¹ isselected from a) substituted or unsubstituted 6-10 membered aryl, b)substituted or unsubstituted 5-6 membered heterocyclyl, c) substitutedor unsubstituted 9-11 membered fused heterocyclyl, d) cycloalkyl, and e)cycloalkenyl, wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH(C₁₋₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl; wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)R³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl; wherein R³ is selected from H,lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, andlower haloalkyl; wherein R⁴ is independently selected from C₂-C₄alkylenyl, C₂-C₄ alkenylenyl and C₂-C₄ alkynylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—; wherein R⁵ isselected from H, lower alkyl, phenyl and lower aralkyl; and wherein R⁶is selected from H or C₁₋₆-alkyl; wherein R¹⁴ is selected from H,phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl;  andpharmaceutically acceptable salts thereof; provided A is not naphthylwhen X is —C(O)NH— and when R¹ is phenyl when Y is —NCH₂— and when R is4-pyridyl; and further provided R is not unsubstituted 2-thienyl,2-pyridyl or 3-pyridyl when Y is —NHCH₂—.
 41. A method of treatingproliferative disorders in a mammal, said method comprisingadministering an effective amount of a compound of Formula I

wherein each of A¹ and A ² is independently C or N; wherein ring A isselected from a) 5- or 6-membered partially saturated heterocyclyl, b)5- or 6-membered heteroaryl, c) 9- or 10-membered fused partiallysaturated heterocyclyl, d) 9-, 10- or 11-membered fused heteroaryl; e)naphthyl, and f) 4-, 5- or 6-membered cycloalkenyl; wherein X isselected from

wherein Z is oxygen or sulfur; wherein Y is selected from

wherein p is 0 to 2, wherein R^(a) and R^(b) are independently selectedfrom H, halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², orwherein R^(a) and R^(b) together form C₃-C₆ cycloalkyl; wherein R^(z) isselected from C₁-C₄ alkylenyl, where one of the CH₂ groups may besubstituted with an oxygen atom or an —NH—; wherein R^(d) is cycloalkyl;wherein R is selected from a) substituted or unsubstituted 5-6 memberedheterocyclyl, and b) substituted or unsubstituted fused 9-, 10- or11-membered heterocyclyl; wherein substituted R is substituted with oneor more substituents independently selected from halo, —OR³, —SR³,—SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³,—NR³C(O)R³, cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, lower alkyl substitutedwith R², cyano, nitro, lower alkenyl and lower alkynyl; wherein R¹ isselected from a) substituted or unsubstituted 6-10 membered aryl, b)substituted or unsubstituted 5-6 membered heterocyclyl, c) substitutedor unsubstituted 9-11 membered fused heterocyclyl, d) cycloalkyl, and e)cycloalkenyl, wherein substituted R¹ is substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substituted phenyl,lower alkyl substituted with R², cyano, nitro, lower alkenyl and loweralkynyl; wherein R² is one or more substituents independently selectedfrom H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,—SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 5-6 membered heterocyclyl,optionally substituted heteroarylalkylenyl, optionally substitutedphenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl,nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, loweralkylaminoalkyl and lower haloalkyl; wherein R³ is selected from H,lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, andlower haloalkyl; wherein R⁴ is independently selected from C₂-C₄alkylenyl, C₂-C₄ alkenylenyl and C₂-C₄ alkynylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—; wherein R⁵ isselected from H, lower alkyl, phenyl and lower aralkyl; and wherein R⁶is selected from H or C₁₋₆-alkyl; wherein R¹⁴ is selected from H,phenyl, 5-6 membered heterocyclyl and C₃-C₆ cycloalkyl;  andpharmaceutically acceptable salts thereof; provided A is not naphthylwhen X is —C(O)NH— and when R¹ is phenyl when Y is —NCH₂— and when R is4-pyridyl; and further provided R is not unsubstituted 2-thienyl,2-pyridyl or 3-pyridyl when Y is —NHCH₂—.
 42. Method of claim 12 whereinthe disorder is inflammation or an inflammation-related disorder.
 43. Acompound of claim 1 having Formula II′

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,oxo, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ isselected from unsubstituted or substituted aryl, cycloalkyl, 5-6membered heteroaryl and 9-10 membered bicyclic and 13-14 memberedtricyclic heterocyclyl, wherein substituted R¹ is substituted with oneor more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, —NHC(O)NH₂, alkylcarbonylamino,aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₂-alkyl andC₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; provided R² is not H, or provided R¹is not heteroaryl or aryl, or provided R is substituted with optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, oroptionally substituted heterocyclyl-C₂₋₄-alkynyl, or provided R¹ issubstituted with optionally substituted phenyloxy, optionallysubstituted 5-6 membered heterocyclyloxy, optionally substituted 5-6membered heterocyclylsulfonyl, optionally substituted 5-6 memberedheterocyclylamino, optionally substituted 5-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy, orC₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy; further provided R is not3-pyridyl when R⁵ is CH₂; and pharmaceutically acceptable isomers andderivatives thereof.
 44. Compound of claim 43 wherein R is selected from4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, pyridazinyl,indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl,2,3-dihydrobenzofuryl, 2-oxo-1,2-dihydroquinol-7-yl, naphthyridinyl andquinozalinyl, where R is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, dimethylaminopropynyl,1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy andethoxy; wherein R¹ is selected from phenyl, tetrahydronaphthyl, indanyl,indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl,quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,quinozalinyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl andbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from bromo, chloro, fluoro, iodo, nitro, amino,cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

 and wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and pharmaceutically acceptable derivativesthereof.
 45. A compound of claim 1 having Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ is aring selected from unsubstituted or substituted 4-6 membered saturatedor partially un-saturated monocyclic heterocyclyl, 9-10 memberedsaturated or partially un-saturated bicyclic heterocyclyl, and 13-14membered saturated or partially un-saturated tricyclic heterocyclyl,wherein substituted R¹ is substituted with one or more substituentsselected from halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable isomers and derivatives thereof.
 46. Acompound of claim 45 wherein R is selected from 4-pyridyl, 3-pyridyl,2-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl,indazolyl, quinolyl, isoquinolyl, benzotriazolyl, naphthyridinyl andquinozalinyl, where R is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, dimethylaminopropynyl,1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy andethoxy; wherein R¹ is selected from 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1H-indolyl,dihydro-benzimidazolyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, andtetrahydroquinolinyl, where R¹ is unsubstituted or substituted with oneor more substituents selected from bromo, chloro, fluoro, iodo, nitro,amino, cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

 and wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and pharmaceutically acceptable derivativesthereof.
 47. A compound of claim 1 having Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ isselected from unsubstituted or substituted aryl, cycloalkyl, 5-6membered heteroaryl and 9-10 membered bicyclic and 13-14 memberedtricyclic heterocyclyl, wherein substituted R¹ is substituted with oneor more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl,C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃₋-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable isomers and derivatives thereof.
 48. Acompound of claim 47 wherein R is selected from 4-pyridyl, 3-pyridyl,2-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl,indazolyl, quinolyl, isoquinolyl, benzotriazolyl, naphthyridinyl andquinozalinyl, where R is unsubstituted or substituted with one or moresubstituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, dimethylaminopropynyl,1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy andethoxy; wherein R¹ is selected from phenyl, tetrahydronaphthyl, indanyl,indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl,quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,quinozalinyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl andbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from bromo, chloro, fluoro, iodo, nitro, amino,cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

 and wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and pharmaceutically acceptable derivativesthereof.
 49. A compound of claim 1 having Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ isselected from unsubstituted or substituted aryl, cycloalkyl, 5-6membered heteroaryl and 9-10 membered bicyclic and 13-14 memberedtricyclic heterocyclyl, wherein substituted R¹ is substituted with oneor more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl,C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; providedR¹ is substituted with optionally substituted phenyloxy, optionallysubstituted 4-6 membered heterocyclyloxy, optionally substituted 4-6membered heterocyclyl-C₁₋₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 4-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy, orC₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy; further provided R is not3-pyridyl when R⁵ is CH₂; and pharmaceutically acceptable isomers andderivatives thereof.
 50. A compound of claim 49 wherein R is selectedfrom 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl,pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,benzotriazolyl, naphthyridinyl and quinozalinyl, where R isunsubstituted or substituted with one or more substituents selected fromchloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl,dimethylaminopropynyl, 1-methylpiperdinylmethoxy,dimethylaminoethoxyethoxy, methoxy and ethoxy; wherein R¹ is selectedfrom phenyl, tetrahydronaphthyl, indanyl, indenyl, naphthyl, cyclohexyl,isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl,pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl,isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl,benzo[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, benzimidazolyl, benzoxazolyl and benzthiazolyl, where R¹ isunsubstituted or substituted with one or more substituents selected frombromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl,Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

 and wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and pharmaceutically acceptable derivativesthereof.
 51. A compound of claim 1 having Formula II′

wherein R is selected from a) unsubstituted or substituted 5- or6-membered non-nitrogen-containing heterocyclyl, and b) unsubstituted orsubstituted 9- or 10-membered fused partially unsaturated heterocyclyl,where R is substituted with one or more substituents selected from halo,amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionallysubstituted heterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ isselected from unsubstituted or substituted aryl, cycloalkyl, 5-6membered heteroaryl and 9-10 membered bicyclic and 13-14 memberedtricyclic heterocyclyl, wherein substituted R¹ is substituted with oneor more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, -NHC(O)NH₂, alkylcarbonylamino, cyano,aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂-3-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl-C₁₋₃-alkyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted 4-6membered heterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable isomers and derivatives thereof.
 52. Acompound of claim 50 wherein R is selected from 2,3-dihydrobenzofuryl,and tetrahydropyran, where R is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, amino, hydroxy, methyl,ethyl, propyl, trifluoromethyl, dimethylaminopropynyl,1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy andethoxy; wherein R¹ is selected from phenyl, tetrahydronaphthyl, indanyl,indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl,thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl,quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,quinozalinyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, benzimidazolyl, dihydro-benzimidazolyl, benzoxazolyl andbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from bromo, chloro, fluoro, iodo, nitro, amino,cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

 and wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and pharmaceutically acceptable derivativesthereof.
 53. A compound of claim 1 having Formula XII

wherein R¹ is selected from unsubstituted or substituted aryl,cycloalkyl, 5-6 membered heteroaryl and 9-10 membered bicyclic and 13-14membered tricyclic heterocyclyl, wherein substituted R¹ is substitutedwith one or more substituents selected from halo, C₁₋₆-alkyl, optionallysubstituted C₃₋₆-cycloalkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionallysubstituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionallysubstituted 4-6 membered heterocyclyl, optionally substituted phenyloxy,optionally substituted 4-6 membered heterocyclyloxy, optionallysubstituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy, optionallysubstituted 4-6 membered heterocyclylsulfonyl, optionally substituted4-6 membered heterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl, halosulfonyl,C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂-3-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andwherein R²⁰ is one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; andpharmaceutically acceptable isomers and derivatives thereof. 54.Compound of claim 53 wherein R¹ is selected from phenyl,tetrahydronaphthyl, indanyl, indenyl, naphthyl, cyclohexyl, isoxazolyl,pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl,pyridazinyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl,naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl,indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl,benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl andbenzthiazolyl, where R¹ is unsubstituted or substituted with one or moresubstituents selected from bromo, chloro, fluoro, iodo, nitro, amino,cyano, aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl,1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl,morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl,piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl,pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl,pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl,1-Boc-pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl,fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc,piperidin-1-ylmethylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl,methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl,3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl,1,1-di(trifluoromethyl)-1-hydroxymethyl,1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl,2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl,1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl,dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy,1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy,1-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy,1-Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy,1-methylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R² isselected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,unsubstituted or substituted phenyl and unsubstituted or substitutedheteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, andpyrazolyl; wherein R⁴ is selected from a direct bond, ethyl, butyl, and

wherein R^(z) is selected from methylenyl, ethylenyl,

 and aminoethylenyl; and wherein R²⁰ is one or more substituentsselected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl,trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy,dimethylaminoethoxyethoxy, methoxy and ethoxy; and pharmaceuticallyacceptable derivatives thereof.
 55. Compound of claim 1 andpharmaceutically acceptable derivatives thereof selected fromN-[3-(Isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-Isoquinolyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-Isopropylphenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;N-[4-(Methylpropyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;{2-[(2-(3-Pyridyl)ethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}carboxamide;N-[5-(tert-Butyl)isoxazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[5-(tert-Butyl)-1-methylpyrazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)(1,3-thiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[5-(tert-Butyl)(1,3,4-thiadiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(4-Hydroxybutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[2-(4-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)}carboxamide;5-Bromo-N-[2-(4-chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Phenoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Methoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Hydroxy-3-ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-(tert-Butyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3-(Trifluoromethyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3-Ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3,4-Dimethylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(1,3-Benzodioxol-5-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Methylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Hydroxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl) amino](3-pyridyl)carboxamide;N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-Bromophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-(Fluorosulfonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(3,5-(Dimethoxy)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(2,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(2-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(2-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(4-(Aminosulphonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(2-Thienyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(Pyridin-2-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)}carboxamide;N-[2-(Pyridin-3-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-[2-(Pyridin-4-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide; N-(4-Phenylbutyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;N-(2-Hydroxy-3-phenoxypropyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;{5-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;2-[(Pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamide;N-(3,4-Dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(Morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-{2-[(tert-Butoxy)carbonylamino]ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(2-Aminoethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-Amino-4-(tert-butyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(Isopropyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-Aminosulfonyl-4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-{3-[(4-Methylpiperazinyl)sulfonyl]phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(1,1,2,2,3,3,4,4,4-Nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(Isopropyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamide;(2-{[2-(2-Pyridylamino)ethyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;{2-[(1-(2-Pyridyl)pyrrolidin-3-yl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamide{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(8-quinolyl)carboxamidehydrochloride;N-[4-(4-Chlorophenoxy)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(2,3,4-trifluorophenyl)carboxamidehydrochloride;N-(2-Naphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(2-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(5,6,7,8-tetrahydronaphthyl)carboxamidehydrochloride;N-(2H-Benzo[3,4-d]1,3-dioxolen-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-Naphthyl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-[3-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-Indan-2-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-[4-(tert-Butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(Methylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;Methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-trifluoromethoxy)phenyl]carboxamide;N-(4-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-Butylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-Iodophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-(Hydroxyethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;Ethyl2-methyl-5-[3-({2-[(4-pyridylmethyl)amino](3-pyridyl)}carbonylamino)phenyl]furan-3-carboxylate;N-(3-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(6-Ethyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(6-Propyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-Hydroxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(Methylethyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3,5-bis(Trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-[4-Chloro-3-(trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(3-Chlorophenyl){2-[(2-(4-pyridyl)ethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(4-Phenoxyphenyl){2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;2-[(Benzo[b]thiophen-3-ylmethyl)amino](3-pyridyl)}-N-(4-phenoxyphenyl)carboxamide;N-(4-Phenoxyphenyl){2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;N-[4-(Methylsulfonyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(1-Acetylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-Indolin-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-Indol-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-Indol-5-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-Indol-7-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-(tert-Butyl)pyrazol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-Phenylpyrazol-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide;N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;N-[1-(2-Piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[1-(2-Piperidylacetyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3,3-Dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-(1-Methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(1,1-Dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamide;N-(4-Bromo-2-fluorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide;{2-[({2-[3-(Dimethylamino)prop-1-ynyl](4-pyridyl)}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide;(2-{[(2-Methoxy(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide;N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)-3-(3-piperidylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)-3-(3-pyrrolidinylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[3-((1E)-4-Pyrrolidinylbut-1-enyl)-4-(tert-butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[1-(2-Morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;N-(4-Chlorophenyl){2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;-{2-[(Pyrimidin-4-ylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;N-[4-(Isopropyl)phenyl]{4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide;2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(tert-butyl)phenyl]carboxamide;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide;(2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;N-[4-(tert-Butyl)phenyl]{6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;N-(1-Bromo(3-isoquinolyl)){6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(4-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(3-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(4-Cyclohexylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride;{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamidehydrochloride;Methyl-4-({2-[(4-pyridylmethyl)amino]-3-pyridy}carbonylamino)benzoatehydrochloride;N-[4-(Isopropyl)phenyl]{2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;N-[4-(tert-Butyl)phenyl]{2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide;{2-[(6-quinolylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;N-(4-chlorophenyl)-3-[(4-pyridinylmethylene)amino]-4-pyridinecarboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;N-phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;N-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;N-(3-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide;N-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3-fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;{6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide;N-(3-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide;N-(3-fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(5-quinolylmethyl)amino](3-pyridyl)}carboxamide;N-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide;N-(4-chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide;N-(4-chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide;2-{[2-(i-Isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(i-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-nicotinamide;2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-methylpiperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;2-({2-[2-(1-Methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-ethylpyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;N-(4-Pentafluoroethyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl-ethylamino)-nicotinamide;N-[3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(4-Boc-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-(1-Boc-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;N-[3,3-Dimethyl-1-(1-Boc-pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;2-{[2-(3-Morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;(S)2-{[2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide;(R)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;(R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;(R)N-[3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(1-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-tert-Butyl-4-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-trifluoromethyl-phenyl)-nicotinamide;2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-tert-butyl-phenyl)-nicotinamide;2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-tert-butyl-isoxazol-5-yl)-nicotinamide;N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;2-[(Pyridin-4-ylmethyl)-amino]-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide;N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide;2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide;N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide;N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide.N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;N-(3-tert-Butyl-isoxazol-5-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;N-(3-trifluoromethylphenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;2-[(2,3-Dihydro-benzofuran-6-ylmethyl)-amino]-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide;(R)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;(S)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[4-Pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[4-Trifluoromethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;(S)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;(R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;(R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(3-Trifluoromethyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;Cu)N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamidewas prepared with pyridine and TEA at 90C.N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide;N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamideN-[4-tert-Butyl-3-(1-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-{4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-[3,3-Dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;N-[3,3-Dimethyl-1-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-([2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;N-(4-Pentafluoroethyl-phenyl)-2-[(pyrimidin-4-ylmethyl)-amino]-nicotinamide;2-{[2-(Azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)nicotinamide;N-(2,3,3-Trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide;N-[3,3-Dimethyl-1,1-dioxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;andN-[2-(2-Dimethylamino-ethyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.56. Compound of claim 1 wherein ring A is selected from dihydropyran,dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl,dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl,dihydro-isoxazolyl, imidazolinyl, pyrazolinyl, triazinyl, thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isoxazolyl, triazolyl and isothiazolyl.
 57. Compound of claim 1 whereinR is selected from substituted or unsubstituted, saturated or partiallysaturated 5-6 membered heterocyclyl, and substituted or unsubstitutedsaturated or partially saturated fused 9-, 10- or 11-memberedheterocyclyl.
 58. Compound of claim 1 wherein R¹ is selected from a)substituted or unsubstituted saturated or partially saturated 5-6membered heterocyclyl, and b) substituted or unsubstituted saturated orpartially saturated 9-11 membered fused heterocyclyl.
 59. Compound ofclaim 58 wherein A is pyridyl.
 60. Compound of claim 1 wherein R¹ isselected from non-nitrogen-containing heteroaryl.
 61. Compound of claim60 wherein R¹ is selected from pyranyl, furyl, thienyl, benzofuryl, andbenzothienyl.
 62. Compound of claim 1 wherein R¹ is substituted with asubstituent selected from —OR³, —SR³, —SO₂R³, —CONHR³, —COR³, —NHR³,—SO₂NHR³, —NHC(O)OR³, —NHC(O)R³ and optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl; and wherein R³ is selected from 5-6membered heterocyclyl.